William Heath

Development of Plasmodium‐specific liver‐resident memory CD8⁺ T cells after heat‐killed sporozoite immunization in mice

Publisher: Wiley

Date: 12-02-2021

DOI: 10.1002/EJI.202048757

Abstract: Malaria remains a major cause of mortality in the world and an efficient vaccine is the best chance of reducing the disease burden. Vaccination strategies for the liver stage of disease that utilise injection of live radiation‐attenuated sporozoites (RAS) confer sterile immunity, which is mediated by CD8 + memory T cells, with liver‐resident memory T cells (T RM ) being particularly important. We have previously described a TCR transgenic mouse, termed PbT‐I, where all CD8 + T cells recognize a specific peptide from Plasmodium . PbT‐I form liver T RM cells upon RAS injection and are capable of protecting mice against challenge infection. Here, we utilize this transgenic system to examine whether nonliving sporozoites, killed by heat treatment (HKS), could trigger the development of Plasmodium ‐specific liver T RM cells. We found that HKS vaccination induced the formation of memory CD8 + T cells in the spleen and liver, and importantly, liver T RM cells were fewer in number than that induced by RAS. Crucially, we showed the number of T RM cells was significantly higher when HKS were combined with the glycolipid α‐galactosylceramide as an adjuvant. In the future, this work could lead to development of an antimalaria vaccination strategy that does not require live sporozoites, providing greater utility.

Erratum to: Single cell analysis of CD4+ T cell differentiation reveals three major cell states and progressive acceleration of proliferation

Publisher: Springer Science and Business Media LLC

Date: 22-06-2016

DOI: 10.1186/S13059-016-0998-9

Targeting antigen to mouse dendritic cells via Clec9A induces potent CD4 T cell responses biased toward a follicular helper phenotype

Publisher: The American Association of Immunologists

Date: 15-07-2011

DOI: 10.4049/JIMMUNOL.1101176

Abstract: Three surface molecules of mouse CD8+ dendritic cells (DCs), also found on the equivalent human DC subpopulation, were compared as targets for Ab-mediated delivery of Ags, a developing strategy for vaccination. For the production of cytotoxic T cells, DEC-205 and Clec9A, but not Clec12A, were effective targets, although only in the presence of adjuvants. For Ab production, however, Clec9A excelled as a target, even in the absence of adjuvant. Potent humoral immunity was a result of the highly specific expression of Clec9A on DCs, which allowed longer residence of targeting Abs in the bloodstream, prolonged DC Ag presentation, and extended CD4 T cell proliferation, all of which drove highly efficient development of follicular helper T cells. Because Clec9A shows a similar expression pattern on human DCs, it has particular promise as a target for vaccines of human application.

Transfer of antigen between migrating and lymph node-resident DCs in peripheral T-cell tolerance and immunity

Publisher: Elsevier BV

Date: 12-2004

DOI: 10.1016/J.IT.2004.09.013

Abstract: Dendritic cells (DCs) consist of a heterogeneous collection of subsets, many with unique phenotypic and functional characteristics. Although certain subsets migrate from peripheral non-lymphoid tissues, there is evidence that antigen presentation can extend to DCs that permanently reside within the lymph node. This Opinion describes this finding in the context of antigen transfer between migrating and lymphoid-resident DCs in cases of T-cell priming and tolerance induction.

The Batman and Robin of liver-stage immunity to malaria

Publisher: Elsevier BV

Date: 2022

DOI: 10.1016/J.PT.2021.11.002

Abstract: Malaria parasites replicate within the liver shortly after infection. This stage can be controlled by CD8 T cells, but which subsets undertake this function is unclear. Lefebvre et al. now elegantly show that effector memory T (T

Resident Memory T Cells and Their Role within the Liver.

Publisher: MDPI AG

Date: 13-11-2020

DOI: 10.3390/IJMS21228565

Abstract: Immunological memory is fundamental to maintain immunity against re-invading pathogens. It is the basis for prolonged protection induced by vaccines and can be mediated by humoral or cellular responses—the latter largely mediated by T cells. Memory T cells belong to different subsets with specialized functions and distributions within the body. They can be broadly separated into circulating memory cells, which pace the entire body through the lymphatics and blood, and tissue-resident memory T (TRM) cells, which are constrained to peripheral tissues. Retained in the tissues where they form, TRM cells provide a frontline defense against reinfection. Here, we review this population of cells with specific attention to the liver, where TRM cells have been found to protect against infections, in particular those by Plasmodium species that cause malaria.

The role of dendritic cell subsets in selection between tolerance and immunity

Publisher: Wiley

Date: 10-2002

DOI: 10.1046/J.1440-1711.2002.01116.X

Abstract: Dendritic cells (DC) are considered nature's adjuvants. They are potent stimulators of naive T cells and key inducers of primary immune responses. In recent times it has become clear that they can also play a central role in the development of T cell tolerance. Further complicating our understanding of DC function is the realization that DC can no longer be viewed as a homogeneous cell type. Rather, they exist as a complex mixture of strikingly different cell populations. The mechanisms that drive the conflicting immunological outcomes of tolerance and immunity have been the subject of intense scrutiny in recent years, most recently in terms of how the various DC subsets are involved in these events. Here we review recent experiments that provide insights into how DC subsets control the outcome of T cell activation and in so doing select between immunity and tolerance induction.

Without peripheral interference, thymic deletion is mediated in a cohort of double-positive cells without classical activation

Publisher: Proceedings of the National Academy of Sciences

Date: 21-01-2003

DOI: 10.1073/PNAS.0237316100

Abstract: Peripheral activation can cause bystander thymocyte death by eliciting a “cytokine storm.” This event complicates in vivo studies using exogenous ligand-induced models of negative selection. A stable transgenic model that selectively eliminates peripheral CD4 cells has allowed us to analyze negative selection as direct cognate events in two T cell receptor transgenic mice, OT-II and DO11. Whereas cognate peptide induced a massive deletion in double-positive (DP) cells in mice with peripheral CD4 cells, this DP deletion was modest in mice lacking peripheral CD4 cells. Using BrdUrd and annexin V staining, we found that negative selection primarily occurs in a cohort of DP cells and the absence of single-positive (SP) cells is largely caused by reduction in the cohort of DP precursors. Moreover, the fates of DP cells and SP cells after antigen exposure were vastly different. Whereas SP cells up-regulated uniformly their CD69 and CD44 levels, increased their cell size, and survived after antigen exposure, DP cells had less CD69 and CD44 up-regulation, no size change, and promptly died. Thus, negative selection represents an “abortive” activation different from activation-induced cell death of mature T cells.

Selected Toll-like Receptor Ligands and Viruses Promote Helper-Independent Cytotoxic T Cell Priming by Upregulating CD40L on Dendritic Cells

Publisher: Elsevier BV

Date: 02-2009

DOI: 10.1016/J.IMMUNI.2008.11.015

Cell‐type‐specific recognition of allogeneic cells by alloreactive cytotoxic T cells: A consequence of peptide‐dependent allorecognition

Publisher: Wiley

Date: 1991

DOI: 10.1002/EJI.1830210123

Abstract: Recently, we provided the first direct evidence that the determinant recognized by some alloreactive cytotoxic T lymphocytes (CTL) clones included an endogenous peptide antigen(s), which could be derived by cyanogen bromide cleavage of cytoplasmic proteins. The studies outlined in this report provide three important findings which confirm and extend our previous results. First, the description of peptide-dependent Kb-specific alloreactive CTL clones is now extended to clones isolated from several responders primed with allogeneic EL4 tumor cells. This indicates that the previously reported results were not unique to the original EL4-primed responder. Second, we establish that peptide-dependent Kb-specific alloreactive CTL clones can be identified after priming with normal allogeneic spleen cells. Thus, induction of peptide-dependent CTL clones is not a unique property of EL4 tumor cells. These results suggest that peptide plays an important role in formation of the allogeneic determinants recognized during graft rejection. Third, these studies reveal that a number of alloreactive CTL clones exhibit cell-type-specific recognition of allogeneic murine target cells. This is consistent with the possibility that some CTL clones recognize peptide antigens that are limited in their tissue distribution. The mechanisms and implications of these findings are discussed.

Putative IKDCs are functionally and developmentally similar to natural killer cells, but not to dendritic cells

Publisher: Rockefeller University Press

Date: 08-10-2007

DOI: 10.1084/JEM.20071351

Abstract: Interferon-producing killer dendritic cells (IKDCs) have been described as possessing the lytic potential of NK cells and the antigen-presenting capacity of dendritic cells (DCs). In this study, we examine the lytic function and antigen-presenting capacity of mouse spleen IKDCs, including those found in DC preparations. IKDCs efficiently killed NK cell targets, without requiring additional activation stimuli. However, in our hands, when exposed to protein antigen or to MHC class II peptide, IKDCs induced little or no T cell proliferation relative to conventional DCs or plasmacytoid DCs, either before or after activation with CpG, or in several disease models. Certain developmental features indicated that IKDCs resembled NK cells more than DCs. IKDCs, like NK cells, did not express the transcription factor PU.1 and were absent from recombinase activating gene-2–null, common γ-chain–null (Rag2−/−Il2rg−/−) mice. When cultured with IL-15 and -18, IKDCs proliferated extensively, like NK cells. Under these conditions, a proportion of expanded IKDCs and NK cells expressed high levels of surface MHC class II. However, even such MHC class II+ IKDCs and NK cells induced poor T cell proliferative responses compared with DCs. Thus, IKDCs resemble NK cells functionally, and neither cell type could be induced to be effective antigen-presenting cells.

Help for cytotoxic-T-cell responses is mediated by CD40 signalling

Publisher: Springer Science and Business Media LLC

Date: 06-1998

DOI: 10.1038/30996

Abstract: Cytotoxic T lymphocytes (CTLs) which carry the CD8 antigen recognize antigens that are presented on target cells by the class I major histocompatibility complex. CTLs are responsible for the killing of antigen-bearing target cells, such as virus-infected cells. Although CTL effectors can act alone when killing target cells, their differentiation from naive CD8-positive T cells is often dependent on 'help' from CD4-positive helper T (TH) cells. Furthermore, for effective CTL priming, this help must be provided in a cognate manner, such that both the TH cell and the CTL recognize antigen on the same antigen-presenting cell. One explanation for this requirement is that TH cells are needed to convert the antigen-presenting cell into a cell that is fully competent to prime CTL. Here we show that signalling through CD40 on the antigen-presenting cells can replace the requirement for TH cells, indicating that T-cell 'help', at least for generation of CTLs by cross-priming, is mediated by signalling through CD40 on the antigen-presenting cell.

Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus

Publisher: Springer Science and Business Media LLC

Date: 22-03-2009

DOI: 10.1038/NI.1718

Abstract: Effective immunity is dependent on long-surviving memory T cells. Various memory subsets make distinct contributions to immune protection, especially in peripheral infection. It has been suggested that T cells in nonlymphoid tissues are important during local infection, although their relationship with populations in the circulation remains poorly defined. Here we describe a unique memory T cell subset present after acute infection with herpes simplex virus that remained resident in the skin and in latently infected sensory ganglia. These T cells were in disequilibrium with the circulating lymphocyte pool and controlled new infection with this virus. Thus, these cells represent an ex le of tissue-resident memory T cells that can provide protective immunity at points of pathogen entry.

Liver-Resident Memory CD8 + T Cells Form a Front-Line Defense against Malaria Liver-Stage Infection

Publisher: Elsevier BV

Date: 10-2016

DOI: 10.1016/J.IMMUNI.2016.08.011

Abstract: In recent years, various intervention strategies have reduced malaria morbidity and mortality, but further improvements probably depend upon development of a broadly protective vaccine. To better understand immune requirement for protection, we examined liver-stage immunity after vaccination with irradiated sporozoites, an effective though logistically difficult vaccine. We identified a population of memory CD8

Differential location of NKT and MAIT cells within lymphoid tissue.

Publisher: Springer Science and Business Media LLC

Date: 08-03-2022

DOI: 10.1038/S41598-022-07704-4

Abstract: Natural Killer T (NKT) cells and Mucosal-Associated Invariant T (MAIT) cells are innate-like T cells that express semi-invariant αβ T cell receptors (TCRs) through which they recognise CD1d and MR1 molecules, respectively, in complex with specific ligands. These cells play important roles in health and disease in many organs, but their precise intra-organ location is not well established. Here, using CD1d and MR1 tetramer staining techniques, we describe the precise location of NKT and MAIT cells in lymphoid and peripheral organs. Within the thymus, NKT cells were concentrated in the medullary side of the corticomedullary junction. In spleen and lymph nodes, NKT cells were mainly localised within T cell zones, although following in vivo activation with the potent NKT-cell ligand α-GalCer, they expanded throughout the spleen. MAIT cells were clearly detectable in Vα19 TCR transgenic mice and were rare but detectable in lymphoid tissue of non-transgenic mice. In contrast to NKT cells, MAIT cells were more closely associated with the B cell zone and red pulp of the spleen. Accordingly, we have provided an extensive analysis of the in situ localisation of NKT and MAIT cells and suggest differences between the intra-organ location of these two cell types.

Cross-presentation of viral and self antigens by skin-derived CD103(+) dendritic cells

Publisher: Springer Science and Business Media LLC

Date: 06-04-2009

DOI: 10.1038/NI.1724

Abstract: Skin-derived dendritic cells (DCs) include Langerhans cells, classical dermal DCs and a langerin-positive CD103(+) dermal subset. We examined their involvement in the presentation of skin-associated viral and self antigens. Only the CD103(+) subset efficiently presented antigens of herpes simplex virus type 1 to naive CD8(+) T cells, although all subsets presented these antigens to CD4(+) T cells. This showed that CD103(+) DCs were the migratory subset most efficient at processing viral antigens into the major histocompatibility complex class I pathway, potentially through cross-presentation. This was supported by data showing only CD103(+) DCs efficiently cross-presented skin-derived self antigens. This indicates CD103(+) DCs are the main migratory subtype able to cross-present viral and self antigens, which identifies another level of specialization for skin DCs.

Coupling and cross-presentation

Publisher: Springer Science and Business Media LLC

Date: 03-2005

DOI: 10.1038/434027A

Peptide antagonists that promote positive selection are inefficient at T cell activation and thymocyte deletion

Publisher: Wiley

Date: 10-1994

DOI: 10.1002/EJI.1830241029

Abstract: We set out to determine whether thymocytes from T cell receptor (TCR) transgenic animals specific for a class I-restricted determinant from ovalbumin (OVA) showed the same fine specificity for antigen-driven deletion in single-cell suspension culture as required for mature T cell activation. The transgenic TCR is specific for the Kb-restricted peptide OVA257-264 (SIINFEKL) which is known to have four TCR contact residues at position 1, 4, 6, and 7 from the crystal structure of this fragment in complex with Kb. OVA257-264 analogs systematically substituted at each of these positions were assayed for their ability to promote immature double-positive thymocyte deletion or mature T cell activation of a cytotoxic T lymphocyte line derived from this transgenic mouse. In the absence of additional antigen-presenting cells, single-cell thymocyte suspensions showed that the specificity for double-positive thymocyte deletion and mature T cell activation was virtually identical, demonstrating a limited cross-reactivity with a number of variants having conservative substitutions at these exposed residues. These peptides were considerably more efficient at both thymic deletion and mature T cell activation than a number of non-conservative substitution analogs known to act as antagonists of OVA257-264 and capable of selecting transgenic T cells in thymic organ culture. Therefore, both peripheral T cell activation and thymic deletion have an overall similar pattern of peptide specificity which differs from that required for positive selection. This suggests that a subset of major histocompatibility complex-presented peptides could promote positive selection without causing either thymic deletion or peripheral activation of those selected T cells.

Classical Type 1 Dendritic Cells Dominate Priming of Th1 Responses to Herpes Simplex Virus Type 1 Skin Infection

Publisher: The American Association of Immunologists

Date: 02-2019

DOI: 10.4049/JIMMUNOL.1800218

Abstract: CD4+ T cell responses are crucial for the control of many intracellular pathogens, yet the requirements for their induction are not fully understood. To better understand the role that various dendritic cell (DC) subtypes play in CD4+ T cell priming, we compared in vivo T cell responses to skin inoculation of mice with infectious or UV-inactivated HSV type 1. Localized infection elicited a Th1 response that was primed in skin-draining lymph nodes involving Ag presentation by migratory dermal and lymph node–resident DC. However, expansion and Th1 differentiation was impaired in response to UV-inactivated virus (UV-HSV), and this defect correlated with a restriction of Ag presentation to migratory CD103– dermal DC. A similar differentiation defect was seen in infected mice lacking CD8α+ and CD103+ classical type 1 DC (cDC1). Finally, Th1 differentiation after UV-HSV inoculation was rescued by targeted Ag delivery to CD8α+ and CD103+ cDC1 using an anti-Clec9A Ab construct. This suggests that Ag presentation by cDC1 is crucial for optimal Th1 immunity to HSV type 1 infection and potentially other pathogens of the skin.

Minimal activation of memory CD8+ T cell by tissue-derived dendritic cells favors the stimulation of naive CD8+ T cells

Publisher: Springer Science and Business Media LLC

Date: 02-09-2007

DOI: 10.1038/NI1505

Abstract: Of the many dendritic cell (DC) subsets, DCs expressing the monomorphic coreceptor CD8 alpha-chain (CD8alpha) are localized permanently in lymphoid organs, whereas 'tissue-derived DCs' remain in nonlymphoid tissues until they 'capture' antigen and then move to local lymph nodes. Here we show that after lung infection, both naive and memory CD8+ 'killer' T cells responded to influenza virus antigens presented by lymph node-resident CD8alpha+ DCs, but only naive cells responded to antigens presented by lung-derived DCs. This difference provides a mechanism for priming naive T cell responses in conditions in which robust memory predominates. Our findings have implications for immunity to pathogens that can mutate their T cell epitopes, such as influenza virus and human immunodeficiency virus, and challenge the long-held view that memory T cells have less-stringent requirements for activation than naive T cells have.

Constitutive, but not inflammatory, cross-presentation is disabled in the pancreas of young mice

Publisher: Wiley

Date: 04-2002

DOI: 10.1002/1521-4141(200204)32:4<1044::AID-IMMU1044>3.0.CO;2-B

Distinct migrating and nonmigrating dendritic cell populations are involved in MHC class I-restricted antigen presentation after lung infection with virus

Publisher: Proceedings of the National Academy of Sciences

Date: 26-05-2004

DOI: 10.1073/PNAS.0402644101

Abstract: During lung infection with virus, airway-derived dendritic cells (DC) have been thought to be the dominant cell type involved in acquisition, transport, and direct antigen presentation for cytotoxic T lymphocyte priming. Contrary to this view, we have found that both an airway-derived CD8α – CD11b – DC subset and distinct CD8α + lymph node resident DC can present class I-restricted antigens after lung infection with influenza virus or herpes simplex virus 1. Presentation by a nonairway-derived DC population argues that cytotoxic T lymphocyte priming may involve interplay between different DC subsets, not all of which originate within the site of infection.

Hair follicles: gatekeepers to the epidermis

Publisher: Springer Science and Business Media LLC

Date: 19-07-2012

DOI: 10.1038/NI.2374

Abstract: Substantial depletion of Langerhans cells leads to their replenishment by bone marrow–derived precursors that access the epidermis through hair follicles, a site of crucial chemokine production.

Infection Programs Sustained Lymphoid Stromal Cell Responses and Shapes Lymph Node Remodeling upon Secondary Challenge

Publisher: Elsevier BV

Date: 2017

DOI: 10.1016/J.CELREP.2016.12.038

Abstract: Lymph nodes (LNs) are constructed of intricate networks of endothelial and mesenchymal stromal cells. How these lymphoid stromal cells (LSCs) regulate lymphoid tissue remodeling and contribute to immune responses remains poorly understood. We performed a comprehensive functional and transcriptional analysis of LSC responses to skin viral infection and found that LSC subsets responded robustly, with different kinetics for distinct pathogens. Recruitment of cells to inflamed LNs induced LSC expansion, while B cells sustained stromal responses in an antigen-independent manner. Infection induced rapid transcriptional responses in LSCs. This transcriptional program was transient, returning to homeostasis within 1 month of infection, yet expanded fibroblastic reticular cell networks persisted for more than 3 months after infection, and this altered LN composition reduced the magnitude of LSC responses to subsequent heterologous infection. Our results reveal the complexity of LSC responses during infection and suggest that lified networks of LN stromal cells support successive immune responses.

A Natural Peptide Antigen within the Plasmodium Ribosomal Protein RPL6 Confers Liver TRM Cell-Mediated Immunity against Malaria in Mice

Publisher: Elsevier BV

Date: 06-2020

DOI: 10.1016/J.CHOM.2020.04.010

Immunology: dangerous liaisons

Publisher: Springer Science and Business Media LLC

Date: 10-2003

DOI: 10.1038/425460A

A key role for ICAM-1 in generating effector cells mediating inflammatory responses

Publisher: Springer Science and Business Media LLC

Date: 06-2001

DOI: 10.1038/88720

Cognate CD4+ T cell licensing of dendritic cells in CD8+ T cell immunity

Publisher: Springer Science and Business Media LLC

Date: 10-10-2004

DOI: 10.1038/NI1129

Abstract: Several studies have indicated that CD8(+) T cells require CD4(+) T cell help for memory formation. Evidence suggests that such help can be antigen independent, challenging whether the 'licensing' of dendritic cells (DCs) by CD4(+) T cells is ever required for cytotoxic T lymphocyte (CTL) responses. We show here that help is essential for the generation of CTL immunity to herpes simplex virus 1 and that CD4(+) T cells mediate help in a cognate, antigen-specific way. We provide direct in vivo evidence for DC licensing by helper T cells and show that licensing is rapid and essential for the formation of effector and memory CTLs. In situations in which DCs are poorly licensed by pathogen-derived signals, our findings suggest that CTL immunity may be heavily dependent on cognate DC licensing.

The threshold for autoimmune T cell killing is influenced by B7-1

Publisher: Wiley

Date: 03-1998

DOI: 10.1002/(SICI)1521-4141(199803)28:03<949::AID-IMMU949>3.0.CO;2-H

Cross-priming: its beginnings

Publisher: The American Association of Immunologists

Date: 08-2010

DOI: 10.4049/JIMMUNOL.1090065

The molecular signature of CD8+ T cells undergoing deletional tolerance

Publisher: American Society of Hematology

Date: 07-05-2009

DOI: 10.1182/BLOOD-2008-10-185223

Abstract: Peripheral tolerance induction is critical for the maintenance of self-tolerance and can be mediated by immunoregulatory T cells or by direct induction of T-cell anergy or deletion. Although the molecular processes underlying anergy have been extensively studied, little is known about the molecular basis for peripheral T-cell deletion. Here, we determined the gene expression signature of peripheral CD8+ T cells undergoing deletional tolerance, relative to those undergoing immunogenic priming or lymphopenia-induced proliferation. From these data, we report the first detailed molecular signature of cells undergoing deletion. Consistent with defective cytolysis, these cells exhibited deficiencies in granzyme up-regulation. Furthermore, they showed antigen-driven Bcl-2 down-regulation and early up-regulation of the proapoptotic protein Bim, consistent with the requirement of this BH3-only protein for peripheral T-cell deletion. Bim up-regulation was paralleled by defective interleukin-7 receptor α (IL-7Rα) chain reexpression, suggesting that Bim-dependent death may be triggered by loss of IL-7/IL-7R signaling. Finally, we observed parallels in molecular signatures between deletion and anergy, suggesting that these tolerance pathways may not be as molecularly distinct as previously surmised.

Immunity or tolerance? That is the question for dendritic cells

Publisher: Springer Science and Business Media LLC

Date: 11-2001

DOI: 10.1038/NI1101-988

Negative selection of semimature CD4⁺8^-HSA ⁺ thymocytes requires the BH3-only protein Bim but is independent of death receptor signaling

Publisher: Proceedings of the National Academy of Sciences

Date: 26-04-2004

DOI: 10.1073/PNAS.0305757101

Abstract: T cell receptor/CD3 ligation induces apoptosis in semimature CD4 + 8 - HSA + thymocytes, and this helps establish immunological tolerance and constitutes one of the safeguards against autoimmune disease. We analyzed several knockout and transgenic mouse lines and found that T cell receptor/CD3-ligation-induced killing of semimature thymocytes occurred independently of Fas and “death receptor” signaling in general but required the proapoptotic BH3-only protein Bim and could be inhibited by Bcl-2. Loss of Apaf-1 or caspase-9, which act downstream of the Bcl-2 family protein family, provided only minor protection, indicating that the “apoptosome” functions as an lifier rather than as an essential initiator of this death program. These results reveal the mechanisms of apoptosis in negative selection of semimature thymocytes and have implications for immunological tolerance and autoimmunity.

The dominant role of CD8⁺dendritic cells in cross-presentation is not dictated by antigen capture

Publisher: Proceedings of the National Academy of Sciences

Date: 11-07-2006

DOI: 10.1073/PNAS.0601956103

Abstract: Mouse spleens contain three populations of conventional (CD11c high ) dendritic cells (DCs) that play distinct functions. The CD8 + DC are unique in that they can present exogenous antigens on their MHC class I molecules, a process known as cross-presentation. It is unclear whether this special ability is because only the CD8 + DC can capture the antigens used in cross-presentation assays, or because this is the only DC population that possesses specialized machinery for cross-presentation. To solve this important question we examined the splenic DC subsets for their ability to both present via MHC class II molecules and cross-present via MHC class I using four different forms of the model antigen ovalbumin (OVA). These forms include a cell-associated form, a soluble form, OVA expressed in bacteria, or OVA bound to latex beads. With the exception of bacterial antigen, which was poorly cross-presented by all DC, all antigenic forms were cross-presented much more efficiently by the CD8 + DC. This pattern could not be attributed simply to a difference in antigen capture because all DC subsets presented the antigen via MHC class II. Indeed, direct assessments of endocytosis showed that CD8 + and CD8 − DC captured comparable amounts of soluble and bead-associated antigen, yet only the CD8 + DC cross-presented these antigenic forms. Our results indicate that cross-presentation requires specialized machinery that is expressed by CD8 + DC but largely absent from CD8 − DC. This conclusion has important implications for the design of vaccination strategies based on antigen targeting to DC.

Helper T cells, dendritic cells and CTL Immunity

Publisher: Wiley

Date: 02-2004

DOI: 10.1111/J.1440-1711.2004.01211.X

Abstract: In this review, we examine the emerging view that all CTL responses depend on CD4 T-cell help for the generation of efficient memory. We further review the evidence that CD4 and CD8 T cells must recognize antigen on the same dendritic cell, and examine why this corecognition is required. Earlier studies have suggested that CD4 T cells must activate the dendritic cell via CD40 to license it for the capacity to prime CTL immunity. More recently, however, CD40 signalling of the CTL has been reported. Here, we argue that the main reason for corecognition of antigen on the dendritic cell may be related to the time taken to activate and release CD4 and CD8 T cells from their priming dendritic cell. CD4 T cells may only be capable of activating one dendritic cell during the period that CD8 T cells are primed. In this case, corecognition of this same dendritic cell would be essential.

Normal proportion and expression of maturation markers in migratory dendritic cells in the absence of germs or Toll‐like receptor signaling

Publisher: Wiley

Date: 20-11-2007

DOI: 10.1038/SJ.ICB.7100125

Abstract: Dendritic cells (DCs) play major roles in immunosurveillance. In peripheral tissues, 'immature' DCs are dedicated to capturing antigens. Detection of pathogens through Toll-like receptors (TLRs) triggers DC migration to the lymph nodes (LNs), where they acquire a 'mature' phenotype specialized at presenting antigens. However, DCs migrate from tissues and mature even in the absence of overt infections. This has been attributed to detection of commensal flora in the skin, the gut or other peripheral tissues in the steady state. To test this assumption, we have analyzed the DCs contained in the lymphoid organs of germ-free mice and of mice lacking the TLR adapter molecules, MyD88 and TRIF. We show that the proportion and expression of maturation markers in DC immigrants in the LNs of these mice are similar to those in normal mice. These results suggest that DC migration from tissues, followed by their phenotypic maturation, is regulated in the steady state by an inherent program of DC differentiation or by the release of low levels of inflammatory signals from normal tissues.

Reactive murine lymph nodes uniquely permit parenchymal access for T cells that enter via the afferent lymphatics

Publisher: Wiley

Date: 17-02-2012

DOI: 10.1002/PATH.3975

Abstract: Whereas naïve T cells access the lymph nodes predominantly via the high endothelial venules, their effector counterparts can also enter via the afferent lymphatics. It is unclear if such cells are confined to the lymphatic spaces during their transit through the lymph node or whether they can access the lymphocyte- and dendritic cell-rich parenchyma with its potentially stimulatory environment. We used a flank HSV inoculation model that featured neuronal-mediated movement of virus to distinct areas of skin to study the lymphatic-mediated transit of activated T cells between different skin-draining lymph nodes. These experiments showed that activated T cells released from the brachial lymph node, draining the primary site of inoculation, entered the downstream axillary lymph node. These activated T cells accessed the subcapsular areas of the axillary lymph node via lymphatic vessels exiting the upstream brachial node regardless of whether the former drained skin that was associated with active infection. However, T cells remained within the sinusoidal network of the axillary lymph node unless it was directly associated with peripheral infection. Thus, activated T cells that enter a given lymph node using the afferent lymphatics do not have automatic access to the parenchyma unless it is a reactive node involved with peripheral inflammation or infection.

Aire-Deficient C57BL/6 Mice Mimicking the Common Human 13-Base Pair Deletion Mutation Present with Only a Mild Autoimmune Phenotype

Publisher: The American Association of Immunologists

Date: 15-03-2009

DOI: 10.4049/JIMMUNOL.0802124

Abstract: Autoimmune regulator (AIRE) is an important transcription regulator that mediates a role in central tolerance via promoting the “promiscuous” expression of tissue-specific Ags in the thymus. Although several mouse models of Aire deficiency have been described, none has analyzed the phenotype induced by a mutation that emulates the common 13-bp deletion in human APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy) by disrupting the first plant homeodomain in exon 8. Aire-deficient mice with a corresponding mutation showed some disturbance of the medullary epithelial compartment, but at the phenotypic level their T cell compartment appeared relatively normal in the thymus and periphery. An increase in the number of activated T cells was evident, and autoantibodies against several organs were detected. At the histological level, lymphocytic infiltration of several organs indicated the development of autoimmunity, although symptoms were mild and the quality of life for Aire-deficient mice appeared equivalent to wild-type littermates, with the exception of male infertility. Vβ and CDR3 length analysis suggested that each Aire-deficient mouse developed its own polyclonal autoimmune repertoire. Finally, given the prevalence of candidiasis in APECED patients, we examined the control of infection with Candida albicans in Aire-deficient mice. No increase in disease susceptibility was found for either oral or systemic infection. These observations support the view that additional genetic and/or environmental factors contribute substantially to the overt nature of autoimmunity associated with Aire mutations, even for mutations identical to those found in humans with APECED.

Local proliferation maintains a stable pool of tissue-resident memory T cells after antiviral recall responses

Publisher: Springer Science and Business Media LLC

Date: 08-01-2018

DOI: 10.1038/S41590-017-0027-5

Abstract: Although tissue-resident memory T cells (T

Intrahepatic activation of naive CD4⁺T cells by liver-resident phagocytic cells

Publisher: The American Association of Immunologists

Date: 09-2014

DOI: 10.4049/JIMMUNOL.1400037

Abstract: Naive T cell activation is normally restricted to the lymphoid organs, in part because of their limited ability to migrate into the parenchyma of peripheral tissues. The liver vasculature is unique, however, and circulating leukocytes within the hepatic sinusoids have direct access to liver-resident cells, which include an abundant population of Kupffer cells. It is well accepted that recognition of cognate Ag within the liver leads to naive CD8+ T cell activation in situ, but it is unclear whether the liver also supports naive CD4+ T cell activation. In this study, we show that naive CD4+ T cells can be activated to proliferate in the liver when cognate Ag expression is induced in hepatocytes by recombinant adeno-associated viral vectors. Ag-specific retention and activation of naive CD4+ T cells within the liver are independent of lymphoid tissues but dependent on a clodronate liposome–sensitive population of liver-resident phagocytic cells. To our knowledge, this study provides the first unequivocal evidence that naive CD4+ T cells can be activated in a nonlymphoid organ. It also gives critical insight into how CD4+ T cells specific for Ag expressed in the liver are recruited to participate in protective or pathological responses during hepatotropic infections and autoimmune liver disease.

Sphingosine 1-phosphate receptor 5 (S1PR5) regulates the peripheral retention of tissue-resident lymphocytes

Publisher: Rockefeller University Press

Date: 22-10-2021

DOI: 10.1084/JEM.20210116

Abstract: Tissue-resident memory T (TRM) cells provide long-lasting immune protection. One of the key events controlling TRM cell development is the local retention of TRM cell precursors coupled to downregulation of molecules necessary for tissue exit. Sphingosine-1-phosphate receptor 5 (S1PR5) is a migratory receptor with an uncharted function in T cells. Here, we show that S1PR5 plays a critical role in T cell infiltration and emigration from peripheral organs, as well as being specifically downregulated in TRM cells. Consequentially, TRM cell development was selectively impaired upon ectopic expression of S1pr5, whereas loss of S1pr5 enhanced skin TRM cell formation by promoting peripheral T cell sequestration. Importantly, we found that T-bet and ZEB2 were required for S1pr5 induction and that local TGF-β signaling was necessary to promote coordinated Tbx21, Zeb2, and S1pr5 downregulation. Moreover, S1PR5-mediated control of tissue residency was conserved across innate and adaptive immune compartments. Together, these results identify the T-bet–ZEB2–S1PR5 axis as a previously unappreciated mechanism modulating the generation of tissue-resident lymphocytes.

Peripheral tissue surveillance and residency by memory T cells

Publisher: Elsevier BV

Date: 2013

DOI: 10.1016/J.IT.2012.08.008

Abstract: T cell immunity has long been described in terms of two circulating memory populations. Central memory T (T(CM)) cells migrate between the secondary lymphoid organs and are capable of mounting a recall proliferative response on pathogen re-encounter, whereas effector memory T (T(EM)) cells traffic between blood and extralymphoid compartments for effective peripheral immune surveillance. It is now clear that there exists a third category of memory cells that never returns to the circulation. These tissue-resident memory T (T(RM)) cells are phenotypically distinct from T(EM) cells, persist in elevated numbers in areas involved in prior infection and have been implicated in various immune phenomena, such as the control of persisting infections and immune disorders in fixed regions of the body.

Rapid recruitment and activation of CD8+ T cells after herpes simplex virus type 1 skin infection.

Publisher: Wiley

Date: 11-05-2011

DOI: 10.1038/ICB.2010.66

Abstract: After localized infection, naive antigen-specific T cells must localize to those lymph nodes (LNs) draining the site of infection before engaging antigen-bearing dendritic cells. Given that naive precursors are initially distributed randomly throughout the secondary lymphoid compartment, it is unclear how long it takes most antigen-specific precursors to mobilize to draining LNs and become recruited into the primary T cell response. Here, we have examined the kinetics of these events, measuring the period over which naive precursors are recruited into the primary T cell response after cutaneous infection with herpes simplex virus type 1 (HSV-1). We show that despite prolonged MHC class-I-restricted antigen presentation, most naive HSV-specific precursors were recruited from the circulation in the first 4 days after inoculation. Furthermore, this prolonged presentation was also not essential for memory development, as truncating the period of antigen presentation to around 4 days did not affect the level of contraction, or long-term stability of the HSV-specific CD8(+) memory T cell pool. Thus, despite initially being dispersed throughout the entire circulation, the recruitment of naive precursors is achieved quite quickly, even when priming is restricted to a small number of draining LNs.

Harnessing liver-resident memory T cells for protection against malaria.

Publisher: Informa UK Limited

Date: 02-2021

DOI: 10.1080/14760584.2021.1881485

Cross-presentation, dendritic cells, tolerance and immunity

Publisher: Annual Reviews

Date: 04-2001

DOI: 10.1146/ANNUREV.IMMUNOL.19.1.47

Abstract: This review examines the role of cross-presentation in tolerance and immunity. We discuss (a) the antigenic requirements for cross-presentation, (b) the phenotype of the antigen presenting cell (APC), (c) the cellular interactions and molecular signals involved in cross-priming, and (d) the factors that direct the immune system toward tolerance or immunity. A large part of this review is dedicated to summarizing our current knowledge of the cross-presenting APC.

CD14 is not involved in the uptake of synthetic CpG oligonucleotides

Publisher: Elsevier BV

Date: 2017

DOI: 10.1016/J.MOLIMM.2016.11.015

Abstract: We have previously shown that DEC205, a surface receptor expressed at high levels on CD8

Display of Native Antigen on cDC1 That Have Spatial Access to Both T and B Cells Underlies Efficient Humoral Vaccination

Publisher: The American Association of Immunologists

Date: 10-2020

DOI: 10.4049/JIMMUNOL.2000549

Abstract: Follicular dendritic cells and macrophages have been strongly implicated in presentation of native Ag to B cells. This property has also occasionally been attributed to conventional dendritic cells (cDC) but is generally masked by their essential role in T cell priming. cDC can be ided into two main subsets, cDC1 and cDC2, with recent evidence suggesting that cDC2 are primarily responsible for initiating B cell and T follicular helper responses. This conclusion is, however, at odds with evidence that targeting Ag to Clec9A (DNGR1), expressed by cDC1, induces strong humoral responses. In this study, we reveal that murine cDC1 interact extensively with B cells at the border of B cell follicles and, when Ag is targeted to Clec9A, can display native Ag for B cell activation. This leads to efficient induction of humoral immunity. Our findings indicate that surface display of native Ag on cDC with access to both T and B cells is key to efficient humoral vaccination.

The CD8+ dendritic cell subset

Publisher: Wiley

Date: 22-02-2010

DOI: 10.1111/J.0105-2896.2009.00870.X

Abstract: Mouse lymphoid tissues contain a subset of dendritic cells (DCs) expressing CD8 alpha together with a pattern of other surface molecules that distinguishes them from other DCs. These molecules include particular Toll-like receptor and C-type lectin pattern recognition receptors. A similar DC subset, although lacking CD8 expression, exists in humans. The mouse CD8(+) DCs are non-migrating resident DCs derived from a precursor, distinct from monocytes, that continuously seeds the lymphoid organs from bone marrow. They differ in several key functions from their CD8(-) DC neighbors. They efficiently cross-present exogenous cell-bound and soluble antigens on major histocompatibility complex class I. On activation, they are major producers of interleukin-12 and stimulate inflammatory responses. In steady state, they have immune regulatory properties and help maintain tolerance to self-tissues. During infection with intracellular pathogens, they become major presenters of pathogen antigens, promoting CD8(+) T-cell responses to the invading pathogens. Targeting vaccine antigens to the CD8(+) DCs has proved an effective way to induce cytotoxic T lymphocytes and antibody responses.

Discrete tissue microenvironments instruct diversity in resident memory T cell function and plasticity

Publisher: Springer Science and Business Media LLC

Date: 23-08-2021

DOI: 10.1038/S41590-021-01004-1

Abstract: Tissue-resident memory T (T

Multiple dendritic cell populations activate CD4+ T cells after viral stimulation

Publisher: Public Library of Science (PLoS)

Date: 27-02-2008

DOI: 10.1371/JOURNAL.PONE.0001691

6″-Modifed α-GalCer-peptide conjugate vaccine candidates protect against liver-stage malaria

Publisher: Royal Society of Chemistry (RSC)

Date: 2022

DOI: 10.1039/D1CB00251A

Abstract: Candidate vaccines comprised of peptide antigen conjugated to 6″-modified α-GalCer analogues generate potent hepatic T RM responses in mice with a single dose inducing protective immunity against malaria in a Plasmodium sporozoite challenge model.

DEC-205 is a cell surface receptor for CpG oligonucleotides

Publisher: Informa UK Limited

Date: 03-2013

DOI: 10.4161/ONCI.23128

Protective immunity to liver-stage malaria

Publisher: Wiley

Date: 10-2016

DOI: 10.1038/CTI.2016.60

Antigen presentation by dendritic cells for B cell activation.

Publisher: Elsevier BV

Date: 06-2019

DOI: 10.1016/J.COI.2019.04.003

Abstract: B cells are efficiently activated by antigens presented on cell membranes, which provide opportunity for receptor cross-linking and antigen capture. The two main cell types implicated in native antigen presentation to B cells are follicular dendritic cells (FDC), which reside in B cell follicles, and CD169

Cerebral Malaria in Mouse and Man

Publisher: Frontiers Media SA

Date: 10-09-2018

DOI: 10.3389/FIMMU.2018.02016

Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance

Publisher: American Society of Hematology

Date: 09-2011

DOI: 10.1182/BLOOD-2010-06-286393

Abstract: To investigate the role of Aire in thymic selection, we examined the cellular requirements for generation of ovalbumin (OVA)–specific CD4 and CD8 T cells in mice expressing OVA under the control of the rat insulin promoter. Aire deficiency reduced the number of mature single-positive OVA-specific CD4+ or CD8+ T cells in the thymus, independent of OVA expression. Importantly, it also contributed in 2 ways to OVA-dependent negative selection depending on the T-cell type. Aire-dependent negative selection of OVA-specific CD8 T cells correlated with Aire-regulated expression of OVA. By contrast, for OVA-specific CD4 T cells, Aire affected tolerance induction by a mechanism that operated independent of the level of OVA expression, controlling access of antigen presenting cells to medullary thymic epithelial cell (mTEC)–expressed OVA. This study supports the view that one mechanism by which Aire controls thymic negative selection is by regulating the indirect presentation of mTEC-derived antigens by thymic dendritic cells. It also indicates that mTECs can mediate tolerance by direct presentation of Aire-regulated antigens to both CD4 and CD8 T cells.

Blood‐stage Plasmodium berghei infection leads to short‐lived parasite‐associated antigen presentation by dendritic cells

Publisher: Wiley

Date: 06-2010

DOI: 10.1002/EJI.200939265

Abstract: Despite extensive evidence that Plasmodium species are capable of stimulating the immune system, the association of malaria with a higher incidence of other infectious diseases and reduced responses to vaccination against unrelated pathogens suggests the existence of immune suppression. Recently, we provided evidence that blood-stage Plasmodium berghei infection leads to suppression of MHC class I-restricted immunity to third party (non-malarial) antigens as a consequence of systemic DC activation. This earlier study did not, however, determine whether reactivity was also impaired to MHC class II-restricted third party antigens or to Plasmodium antigens themselves. Here, we show that while P. berghei-expressed antigens were presented early in infection, there was a rapid decline in presentation within 4 days, paralleling impairment in MHC class I- and II-restricted presentation of third party antigens. This provides important evidence that P. berghei not only causes immunosuppression to subsequently encountered third party antigens, but also rapidly limits the capacity to generate effective parasite-specific immunity.

Kruppel-ling of IRF4-Dependent DCs into Two Functionally Distinct DC Subsets

Publisher: Elsevier BV

Date: 05-2015

DOI: 10.1016/J.IMMUNI.2015.04.020

Abstract: IRF4-dependent DCs have been associated with induction of both Th1 and Th17 cells. In this issue of Immunity, Tussiwand et al. (2015) demonstrate that a dependence on KLF4 identifies a subset of IRF4-dependent DC that preferentially promotes Th2 cell differentiation.

Glycolipid-peptide vaccination induces liver-resident memory CD8⁺ T cells that protect against rodent malaria

Publisher: American Association for the Advancement of Science (AAAS)

Date: 26-06-2020

DOI: 10.1126/SCIIMMUNOL.AAZ8035

Abstract: Glycolipid-peptide conjugate vaccines protect against rodent malaria by generating large numbers of liver CD8 + T RM cells.

CD4(+) T-cell help amplifies innate signals for primary CD8(+) T-cell immunity

Publisher: Wiley

Date: 20-06-2016

DOI: 10.1111/IMR.12426

Abstract: CD8(+) T cells provide an important component of protection against intracellular infections and cancer. Immune responses by these T cells involve a primary phase of effector expansion and differentiation, followed by a contraction phase leading to memory formation and, if antigen is re-encountered, a secondary expansion phase with more rapid differentiation. Both primary and secondary phases of CD8(+) T-cell immunity have been shown to depend on CD4(+) T-cell help, although during certain infections the primary phase is variable in this requirement. One explanation for such variability relates to the strength of associated inflammatory signals, with weak signals requiring help. Here, we focus on our studies that have dissected the requirements for help in the primary phase of the CTL response to herpes simplex virus, elucidating intricate interactions and communications between CD4(+) T cells, various dendritic cell subsets, and CD8(+) T cells. We place our studies in the context of others and describe a simple model of help where CD40 signaling lifies innate signals to enable efficient CD8(+) T-cell expansion and differentiation. This model facilitates CTL induction to various different agents, without altering the qualitative innate signals that direct other important arms of immunity.

Differential Migration of Epidermal and Dermal Dendritic Cells during Skin Infection

Publisher: The American Association of Immunologists

Date: 03-2009

DOI: 10.4049/JIMMUNOL.0802950

Abstract: Dendritic cells (DCs) are extremely heterogeneous, most evident in the skin where a variety of different subsets have been identified in recent years. DCs of healthy skin include a number of distinct populations in the dermal layer as well as the well-characterized Langerhans cells (LCs) of the epidermis. These steady-state populations are augmented during bouts of local inflammation by additional monocyte-derived DCs. In an effort to better understand the distinction between the different subsets, we examined their behavior following skin infection with HSV. LC emigration rapidly followed appearance of virus in the skin and resulted in depopulation of regions in areas surrounding infected nerve endings. A separate DC population was found to accumulate within the dermis under patches of active epidermal infection with at least some derived from blood monocyte precursors. Ag-positive DCs could occasionally be found in these dermal accumulations, although they represented a minority of DCs in these areas. In addition, infected DCs appeared compromised in their trafficking capabilities and were largely absent from the migrating population. On resolution of skin disease, LCs repopulated the reformed epidermis and these were of mixed origin, with around half entering from the circulation and the remainder derived from local progenitors. Overall, our results show a range of migrational complexities between distinct skin DC populations as a consequence of localized infection.

Defective TCR expression in transgenic mice constructed using cDNA-based alpha- and beta-chain genes under the control of heterologous regulatory elements

Publisher: Wiley

Date: 02-1998

DOI: 10.1046/J.1440-1711.1998.00709.X

Abstract: We describe the generation of ovalbumin (OVA)-specific, MHC class II-restricted alpha beta T cell receptor (TCR) transgenic mice. Initial attempts at generating these transgenic mice utilized heterologous regulatory elements to drive the expression of cDNA genes encoding the separate alpha- and beta-chains of the TCR. Unexpectedly, T cells bearing the transgenic alpha beta TCR failed to emerge from the thymus in these mice, although the transgenes did modify endogenous TCR expression. However, subsequent modification of the approach which enabled expression of the TCR beta-chain under the control of its natural regulatory elements generated mice whose peripheral T cells expressed the transgenic TCR and were capable of antigen-dependent proliferation. These results show that successful generation of MHC class II-restricted, OVA-specific alpha beta TCR transgenic mice was dependent upon combining cDNA- and genomic DNA-based constructs for expression of the respective alpha- and beta-chains of the TCR.

CTL response compensation for the loss of an immunodominant class I-restricted HSV-1 determinant.

Publisher: Wiley

Date: 12-2006

DOI: 10.1111/J.1440-1711.2006.01469.X

Abstract: The T-cell response to even complex pathogens is often focused on only a handful of immunodominant determinants. Such narrow responses provoke a selective pressure that can drive the emergence of CTL escape variants, raising the question of whether a broader response, targeting multiple non-dominant peptides may be more beneficial. To examine the ability of the T-cell repertoire to respond to non-dominant determinants, we have investigated how mutating the dominant peptide in HSV affects the magnitude of the CD8+ T-cell response. We found that the CTL response to HSV lacking the dominant peptide was only modestly reduced compared with the wild-type virus and, surprisingly, this compensation occurred without any enhancement in the response to an established minor epitope. These findings are supportive of a malleable T-cell repertoire that can elicit strong responses to alternate, unknown determinants in the absence of the dominant response.

mRNA vaccine against malaria tailored for liver-resident memory T cells

Publisher: Springer Science and Business Media LLC

Date: 20-07-2023

DOI: 10.1038/S41590-023-01562-6

Marginal zone B cells acquire dendritic cell functions by trogocytosis

Publisher: American Association for the Advancement of Science (AAAS)

Date: 11-02-2022

DOI: 10.1126/SCIENCE.ABF7470

Abstract: Marginal zone (MZ) B cells produce broad-spectrum antibodies that protect against infection early in life. In some instances, antibody production requires MZ B cells to display pathogen antigens bound to major histocompatibility complex class II (MHC II) molecules to T cells. We describe the trogocytic acquisition of these molecules from conventional dendritic cells (cDCs). Complement component 3 (C3) binds to murine and human MHC II on cDCs. MZ B cells recognize C3 with complement receptor 2 (CR2) and trogocytose the MHC II–C3 complexes, which become exposed on their cell surface. The ubiquitin ligase MARCH1 limits the number of MHC II–C3 complexes displayed on cDCs to prevent their elimination through excessive trogocytosis. Capture of C3 by MHC II thus enables the transfer of cDC-like properties to MZ B cells.

T Cell Help Amplifies Innate Signals in CD8(+) DCs for Optimal CD8(+) T Cell Priming

Publisher: Elsevier BV

Date: 2016

DOI: 10.1016/J.CELREP.2015.12.058

Abstract: DCs often require stimulation from CD4(+) T cells to propagate CD8(+) T cell responses, but precisely how T cell help optimizes the priming capacity of DCs and why this appears to differ between varying types of CD8(+) T cell immunity remains unclear. We show that CD8(+) T cell priming upon HSV-1 skin infection depended on DCs receiving stimulation from both IFN-α/β and CD4(+) T cells to provide IL-15. This was not an additive effect but resulted from CD4(+) T cells lifying DC production of IL-15 in response to IFN-α/β. We also observed that increased innate stimulation reversed the helper dependence of CD8(+) T cell priming and that the innate stimulus, rather than the CD4(+) T cells themselves, determined how "help'" was integrated into the priming response by DCs. These findings identify T cell help as a flexible means to lify varying suboptimal innate signals in DCs.

Differential MHC class II synthesis and ubiquitination confers distinct antigen-presenting properties on conventional and plasmacytoid dendritic cells

Publisher: Springer Science and Business Media LLC

Date: 12-10-2008

DOI: 10.1038/NI.1665

Abstract: The importance of conventional dendritic cells (cDCs) in the processing and presentation of antigen is well established, but the contribution of plasmacytoid dendritic cells (pDCs) to these processes, and hence to T cell immunity, remains unclear. Here we showed that unlike cDCs, pDCs continued to synthesize major histocompatibility complex (MHC) class II molecules and the MHC class II ubiquitin ligase MARCH1 long after activation. Sustained MHC class II-peptide complex formation, ubiquitination and turnover rendered pDCs inefficient in the presentation of exogenous antigens but enabled pDCs to continuously present endogenous viral antigens in their activated state. As the antigen-presenting abilities of cDCs and pDCs are fundamentally distinct, these two cell types may activate largely nonoverlapping repertoires of CD4(+) T cells.

Maintenance of T cell function in the face of chronic antigen stimulation and repeated reactivation for a latent virus infection.

Publisher: The American Association of Immunologists

Date: 03-2012

DOI: 10.4049/JIMMUNOL.1102719

Abstract: Persisting infections are often associated with chronic T cell activation. For certain pathogens, this can lead to T cell exhaustion and survival of what is otherwise a cleared infection. In contrast, for herpesviruses, T cells never eliminate infection once it is established. Instead, effective immunity appears to maintain these pathogens in a state of latency. We used infection with HSV to examine whether effector-type T cells undergoing chronic stimulation retained functional and proliferative capacity during latency and subsequent reactivation. We found that latency-associated T cells exhibited a polyfunctional phenotype and could secrete a range of effector cytokines. These T cells were also capable of mounting a recall proliferative response on HSV reactivation and could do so repeatedly. Thus, for this latent infection, T cells subjected to chronic Ag stimulation and periodic reactivation retain the ability to respond to local virus challenge.

Dendritic cell subsets in primary and secondary T cell responses at body surfaces

Publisher: Springer Science and Business Media LLC

Date: 16-11-2009

DOI: 10.1038/NI.1822

Abstract: We examine the role of dendritic cells subsets in immunity to peripheral infections, with emphasis on the differences in the regulation of primary and secondary T cell responses to viruses. Our major focus is on new developments in the understanding of immunity to infections of the skin and lung, which are crucial entry points for a variety of infectious pathogens. Initially we describe a erse network of dendritic cell subsets, but then we argue for a more generalized model of reduced complexity.

CD8+ T Cells from a Novel T Cell Receptor Transgenic Mouse Induce Liver-Stage Immunity That Can Be Boosted by Blood-Stage Infection in Rodent Malaria

Publisher: Public Library of Science (PLoS)

Date: 22-05-2014

DOI: 10.1371/JOURNAL.PPAT.1004135

Targeting Dendritic Cells in vivo for Cancer Therapy

Publisher: Frontiers Media SA

Date: 2012

DOI: 10.3389/FIMMU.2012.00013

Loss of antiviral cytotoxic T-lymphocyte activity during high-level antigen stimulation

Publisher: Mary Ann Liebert Inc

Date: 1998

DOI: 10.1089/VIM.1998.11.183

Abstract: High levels of antigenic stimulation can result in deactivation of CD8+ T cells through a variety of mechanisms, including insufficient T-cell help. In the present study, an adoptive transfer system was established in which ovalbumin (OVA)-specific CD8+ T cells were transferred to irradiated mice infected with a recombinant vaccinia virus encoding OVA (VV-OVA). Prolonged activation of OVA-specific CD8+ T cells resulted in a proliferative block in these cells, although cytotoxic function was maintained. Unlike naive and recently activated OVA-specific T cells, these nonproliferative cytotoxic CD8+ T cells did not have antiviral activity following further transfer to mice infected with VV-OVA. Provision of interleukin-2 (IL-2) at the site of virus infection using a recombinant virus encoding antigen and IL-2, as well as the addition of helper T cells, had no effect on the generation of these dysfunctional T cells. Thus, there was no evidence that lack of T-cell help was responsible for CD8+ T-cell deactivation in this model.

The use of carboxyfluorescein diacetate succinimidyl ester to determine the site, duration and cell type responsible for antigen presentation in vivo

Publisher: Wiley

Date: 12-1999

DOI: 10.1046/J.1440-1711.1999.00868.X

Abstract: This report examines the use of 5-(and-6)-carboxyfluorescein diacetate succinimidyl ester (CFSE) to determine the site, duration and cell type responsible for antigen presentation in vivo. Evidence that CFSE-labelled T cells can be used to determine where various types of antigens are presented, including auto-antigens, oral antigens and cell-associated foreign antigens, is provided. Using this technique, the length of time antigen is presented after acquisition by APC was measured. Finally, CFSE labelling was used to identify the origin of the APC responsible for different forms of antigen presentation.

Systemic Inflammation Suppresses Lymphoid Tissue Remodeling and B Cell Immunity during Concomitant Local Infection.

Publisher: Elsevier BV

Date: 12-2020

DOI: 10.1016/J.CELREP.2020.108567

NLRC4 inflammasomes in dendritic cells regulate noncognate effector function by memory CD8+ T cells

Publisher: Springer Science and Business Media LLC

Date: 08-01-2012

DOI: 10.1038/NI.2195

Abstract: Memory T cells exert antigen-independent effector functions, but how these responses are regulated is unclear. We discovered an in vivo link between flagellin-induced NLRC4 inflammasome activation in splenic dendritic cells (DCs) and host protective interferon-γ (IFN-γ) secretion by noncognate memory CD8(+) T cells, which could be activated by Salmonella enterica serovar Typhimurium, Yersinia pseudotuberculosis and Pseudomonas aeruginosa. We show that CD8α(+) DCs were particularly efficient at sensing bacterial flagellin through NLRC4 inflammasomes. Although this activation released interleukin 18 (IL-18) and IL-1β, only IL-18 was required for IFN-γ production by memory CD8(+) T cells. Conversely, only the release of IL-1β, but not IL-18, depended on priming signals mediated by Toll-like receptors. These findings provide a comprehensive mechanistic framework for the regulation of noncognate memory T cell responses during bacterial immunity.

Persistence of skin-resident memory T cells within an epidermal niche

Publisher: Proceedings of the National Academy of Sciences

Date: 24-03-2014

DOI: 10.1073/PNAS.1322292111

Abstract: Tissue-resident memory T cells (T RM ) form in the skin where they are retained and can protect against subsequent infection. Using a combination of intravital imaging and mathematical modeling of skin T RM that form after cutaneous herpes simplex virus 1 infection, we reveal that these memory T cells persist at the site of infection for the life of a mouse owing to slow random migration. We also report that T RM compete with dendritic epidermal γδ T cells in skin for local survival signals, suggesting that T cells compete for space within an epidermal niche.

Distinct resident and recirculating memory T cell subsets in non-lymphoid tissues

Publisher: Elsevier BV

Date: 06-2013

DOI: 10.1016/J.COI.2013.05.007

Abstract: Antigen experienced or memory T cells make a critical contribution to immunity against infection. Many pathogens colonise non-lymphoid tissues and memory T cells in these compartments can deal with such localised infections. Emerging data show that there are at least two phenotypically distinct peripheral T cell subsets, one permanently resident and one recirculating between tissues and blood. A full appreciation of the T cells in the non-lymphoid memory pool and their relationship to those in the circulation is an important step in understanding how to generate and exploit effective peripheral immunity for the purpose of infection control.

Optimization of TCR transgenic T cells for in vivo tracking of immune responses.

Publisher: Wiley

Date: 05-06-2007

DOI: 10.1038/SJ.ICB.7100076

Abstract: T-cell receptor (TCR) transgenic mice have proven useful for the study of various immune parameters. Despite this, it has been suggested that transferred T cells respond differently to their endogenous counterparts at least in terms of conversion to antigen-experienced populations bearing memory cell markers. Here, we have compared the response of TCR transgenic T cells to endogenous populations within the context of infection with herpes simplex virus. We found that adoptive transfer at numbers approaching those of the endogenous virus-specific subset results in a response with similar kinetics, magnitude and memory subset conversion. This suggests that this form of optimized T-cell transfer remains a useful means of tracking antiviral immune responses.

IFN Regulatory Factor 3 Balances Th1 and T Follicular Helper Immunity during Nonlethal Blood-Stage Plasmodium Infection

Publisher: The American Association of Immunologists

Date: 15-02-2018

DOI: 10.4049/JIMMUNOL.1700782

Abstract: Differentiation of CD4+ Th cells is critical for immunity to malaria. Several innate immune signaling pathways have been implicated in the detection of blood-stage Plasmodium parasites, yet their influence over Th cell immunity remains unclear. In this study, we used Plasmodium-reactive TCR transgenic CD4+ T cells, termed PbTII cells, during nonlethal P. chabaudi chabaudi AS and P. yoelii 17XNL infection in mice, to examine Th cell development in vivo. We found no role for caspase1/11, stimulator of IFN genes, or mitochondrial antiviral-signaling protein, and only modest roles for MyD88 and TRIF-dependent signaling in controlling PbTII cell expansion. In contrast, IFN regulatory factor 3 (IRF3) was important for supporting PbTII expansion, promoting Th1 over T follicular helper (Tfh) differentiation, and controlling parasites during the first week of infection. IRF3 was not required for early priming by conventional dendritic cells, but was essential for promoting CXCL9 and MHC class II expression by inflammatory monocytes that supported PbTII responses in the spleen. Thereafter, IRF3-deficiency boosted Tfh responses, germinal center B cell and memory B cell development, parasite-specific Ab production, and resolution of infection. We also noted a B cell–intrinsic role for IRF3 in regulating humoral immune responses. Thus, we revealed roles for IRF3 in balancing Th1- and Tfh-dependent immunity during nonlethal infection with blood-stage Plasmodium parasites.

The C-type lectin Clec12A present on mouse and human dendritic cells can serve as a target for antigen delivery and enhancement of antibody responses.

Publisher: The American Association of Immunologists

Date: 15-06-2009

DOI: 10.4049/JIMMUNOL.0900464

Abstract: We have cloned the mouse and human C-type lectin Clec12A, expressed both, and produced mAb recognizing both. Mouse Clec12A is highly expressed on splenic CD8+ dendritic cells (DC) and plasmacytoid DC. A proportion of CD8−DC also expresses lower levels of Clec12A, as do monocytes, macrophages, and B cells. Human CLEC12A, like the mouse counterpart, is expressed on blood monocytes and DC, including pDC and BDCA-3+DC, the proposed equivalent of mouse CD8+DC. To determine whether Ag targeted to Clec12A could induce immune responses, mice were injected with a rat mAb recognizing Clec12A, or a control rat mAb, then production of anti-rat Ig was measured. Anti-Clec12A mAb alone produced only moderate responses, but these were lified by coinjecting only small amounts of LPS as a DC activation agent. Furthermore, when OVA was conjugated to anti-Clec12A mAb, OVA-specific T cells were induced to proliferate. This Ag presentation to naive T cells was due to targeting conventional DC, because their ablation eliminated T cell activation. The potent Ab responses induced using microgram amounts of anti-Clec12A and minimal amounts of adjuvant demonstrate that this molecule can be used as an Ag-delivery target to enhance Ab responses to vaccines.

Unresponsiveness to inhaled antigen is governed by conventional dendritic cells and overridden during infection by monocytes

Publisher: American Association for the Advancement of Science (AAAS)

Date: 08-10-2020

DOI: 10.1126/SCIIMMUNOL.ABB5439

Abstract: Immunity to inhaled antigens is governed by inflammatory signals that alter the composition of DC subsets within the NALTs.

Granzyme B expression by CD8+ T cells is required for the development of experimental cerebral malaria

Publisher: The American Association of Immunologists

Date: 06-2011

DOI: 10.4049/JIMMUNOL.1003955

Abstract: Parasite burden predicts disease severity in malaria and risk of death in cerebral malaria patients. In murine experimental cerebral malaria (ECM), parasite burden and CD8+ T cells promote disease by mechanisms that are not fully understood. We found that the majority of brain-recruited CD8+ T cells expressed granzyme B (GzmB). Furthermore, gzmB−/− mice harbored reduced parasite numbers in the brain as a consequence of enhanced antiparasitic CD4+ T cell responses and were protected from ECM. We showed in these ECM-resistant mice that adoptively transferred, Ag-specific CD8+ T cells migrated to the brain, but did not induce ECM until a critical Ag threshold was reached. ECM induction was exquisitely dependent on Ag-specific CD8+ T cell-derived perforin and GzmB, but not IFN-γ. In wild-type mice, full activation of brain-recruited CD8+ T cells also depended on a critical number of parasites in this tissue, which in turn, was sustained by these tissue-recruited cells. Thus, an interdependent relationship between parasite burden and CD8+ T cells dictates the onset of perforin/GzmB-mediated ECM.

Effective Priming of Herpes Simplex Virus-Specific CD8 + T Cells In Vivo Does Not Require Infected Dendritic Cells

Publisher: American Society for Microbiology

Date: 02-2017

DOI: 10.1128/JVI.01508-17

Abstract: Resolution of virus infections depends on the priming of virus-specific CD8 + T cells by dendritic cells (DC). While this process requires major histocompatibility complex (MHC) class I-restricted antigen presentation by DC, the relative contribution to CD8 + T cell priming by infected DC is less clear. We have addressed this question in the context of a peripheral infection with herpes simplex virus 1 (HSV). Assessing the endogenous, polyclonal HSV-specific CD8 + T cell response, we found that effective in vivo T cell priming depended on the presence of DC subsets specialized in cross-presentation, while Langerhans cells and plasmacytoid DC were dispensable. Utilizing a novel mouse model that allows for the in vivo elimination of infected DC, we also demonstrated in vivo that this requirement for cross-presenting DC was not related to their infection but instead reflected their capacity to cross-present HSV-derived antigen. Taking the results together, this study shows that infected DC are not required for effective CD8 + T cell priming during a peripheral virus infection. IMPORTANCE The ability of some DC to present viral antigen to CD8 + T cells without being infected is thought to enable the host to induce killer T cells even when viruses evade or kill infected DC. However, direct experimental in vivo proof for this notion has remained elusive. The work described in this study characterizes the role that different DC play in the induction of virus-specific killer T cell responses and, critically, introduces a novel mouse model that allows for the selective elimination of infected DC in vivo . Our finding that HSV-specific CD8 + T cells can be fully primed in the absence of DC infection shows that cross-presentation by DC is indeed sufficient for effective CD8 + T cell priming during a peripheral virus infection.

Breakdown in repression of IFN-γ mRNA leads to accumulation of self-reactive effector CD8+ T cells

Publisher: The American Association of Immunologists

Date: 15-07-2012

DOI: 10.4049/JIMMUNOL.1102432

Abstract: Tight regulation of virus-induced cytotoxic effector CD8+ T cells is essential to prevent immunopathology. Naturally occurring effector CD8+ T cells, with a KLRG1hi CD62Llo phenotype typical of short-lived effector CD8+ T cells (SLECs), can be found in increased numbers in autoimmune-prone mice, most notably in mice homozygous for the san allele of Roquin. These SLEC-like cells were able to trigger autoimmune diabetes in a susceptible background. When Roquin is mutated (Roquinsan), effector CD8+ T cells accumulate in a cell-autonomous manner, most prominently as SLEC-like effectors. Excessive IFN-γ promotes the accumulation of SLEC-like cells, increases their T-bet expression, and enhances their granzyme B production in vivo. We show that overexpression of IFN-γ was caused by failed posttranscriptional repression of Ifng mRNA. This study identifies a novel mechanism that prevents accumulation of self-reactive cytotoxic effectors, highlighting the importance of regulating Ifng mRNA stability to maintain CD8+ T cell homeostasis and prevent CD8-mediated autoimmunity.

Autoimmune diabetes as a consequence of locally produced interleukin-2

Publisher: Springer Science and Business Media LLC

Date: 10-1992

DOI: 10.1038/359547A0

Abstract: During cell differentiation in the thymus, self-reactive T cells can be generated. The majority of these seem to be deleted after intrathymic encounter with the relevant autoantigen. As all self antigens are unlikely to be present in the thymus, some autoreactive T cells may escape censorship. Here we study the fate of these cells using transgenic mice expressing the class I molecule H-2Kb (Kb) in the insulin-producing beta-cells of the pancreas. These mice were crossed with mice transgenic for genes encoding a Kb-specific T-cell antigen receptor (TCR) which could be detected using a clonotype-specific monoclonal antibody. Although T cells expressing the highest level of transgenic TCR were deleted intrathymically in double-transgenic mice, Kb-specific T cells were detected in the periphery. These cells caused the rejection of Kb-expressing skin grafts, but ignored islet Kb antigens even after priming. But when double-transgenic mice were crossed with transgenic mice expressing the lymphokine interleukin-2 in the pancreatic beta-cells, there was a rapid onset of diabetes. These results indicate that autoreactive T cells that ignore self antigens may cause autoimmune diabetes when provided with exogenous 'help' in the form of interleukin-2.

Immunology: education and promiscuity

Publisher: Springer Science and Business Media LLC

Date: 12-2002

DOI: 10.1038/420468A

Down-modulation of CD8 beta-chain in response to an altered peptide ligand enables developing thymocytes to escape negative selection

Publisher: Elsevier BV

Date: 02-1997

DOI: 10.1006/CIMM.1996.1054

Abstract: Mice expressing a Kb-restricted transgenic T cell receptor (TCR) and a naturally occurring MHC class I variant molecule, Kbm8, were used to study thymic selection. The transgenic TCR was specific for the major peptide determinant from ovalbumin (OVA(257-264)), while Kbm8 has a mutation that alters the position 2 binding pocket of the Kb molecule, abolishing antigenic peptide presentation and positive selection of transgenic T cells. Peptide presentation was restored by identifying a position 2 analog peptide with Kbm8-binding capacity. In combination with Kbm8, the E2 peptide variant was capable of deleting immature double-positive thymocytes in suspension culture. Similarly, addition of exogenous E2 peptide to fetal thymic organ culture resulted in efficient deletion of double-positive thymocytes. However, there remained a population of CD8 single-positive T cells that exhibited impaired responsiveness to the antigenic peptide and lacked expression of the CD8 beta-chain. These results suggest a mechanism whereby developing thymocytes bearing an alphabetaTCR can modify their expression of the CD8 coreceptor to escape thymic deletion and achieve self-tolerance.

Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation.

Publisher: Proceedings of the National Academy of Sciences

Date: 16-04-2012

DOI: 10.1073/PNAS.1202288109

Abstract: Although circulating memory T cells provide enhanced protection against pathogen challenge, they often fail to do so if infection is localized to peripheral or extralymphoid compartments. In those cases, it is T cells already resident at the site of virus challenge that offer superior immune protection. These tissue-resident memory T (T RM ) cells are identified by their expression of the α-chain from the integrin α E (CD103)β 7 , and can exist in disequilibrium with the blood, remaining in the local environment long after peripheral infections subside. In this study, we demonstrate that long-lived intraepithelial CD103 + CD8 + T RM cells can be generated in the absence of in situ antigen recognition. Local inflammation in skin and mucosa alone resulted in enhanced recruitment of effector populations and their conversion to the T RM phenotype. The CD8 + T RM cells lodged in these barrier tissues provided long-lived protection against local challenge with herpes simplex virus in skin and vagina challenge models, and were clearly superior to the circulating memory T-cell cohort. The results demonstrate that peripheral T RM cells can be generated and survive in the absence of local antigen presentation and provide a powerful means of achieving immune protection against peripheral infection.

Blood-Stage Plasmodium berghei Infection Generates a Potent, Specific CD8+ T-Cell Response Despite Residence Largely in Cells Lacking MHC I Processing Machinery

Publisher: Oxford University Press (OUP)

Date: 13-10-2011

DOI: 10.1093/INFDIS/JIR656

Abstract: Murine cerebral malaria is a complex disease caused by Plasmodium berghei ANKA infection. Several cell types, including CD8(+) T cells, are essential effectors of disease. Although the use of transgenic parasites expressing model antigens has revealed the induction of cytotoxic T lymphocytes (CTL) specific for these model antigens, there is no direct evidence for a response to authentic blood-stage parasite antigens, nor any knowledge of its magnitude. Our studies show that there is a dramatic primary parasite-specific CTL response, akin to viral immunity, reaching approximately 30% of splenic CD8(+) T cells, with many producing interferon-γ and tumor necrosis factor-α. These cells express granzyme B and other markers of specific responders, are cytolytic, and respond to a broad array of major histocompatibility complex (MHC) I-restricted epitopes, 5 of which are identified here. Our studies indicate that vigorous CTL responses can be induced to pathogens even when they largely reside in red blood cells, which lack MHC I processing machinery.

Proteomic and metabolomic analyses of mitochondrial complex I-deficient mouse model generated by spontaneous B2 short interspersed nuclear element (SINE) insertion into NADH dehydrogenase (ubiquinone) Fe-S protein 4 (Ndufs4) gene

Publisher: Elsevier BV

Date: 06-2012

DOI: 10.1074/JBC.M111.327601

Dendritic cell-induced memory T cell activation in nonlymphoid tissues

Publisher: American Association for the Advancement of Science (AAAS)

Date: 11-01-2008

DOI: 10.1126/SCIENCE.1151869

Abstract: Secondary lymphoid organs are dominant sites of T cell activation, although many T cells are subsequently retained within peripheral tissues. Currently, these nonlymphoid compartments are viewed as sites only of effector T cell function, without the involvement of renewed induction of immunity via the interactions with professional antigen-presenting cells. We describe a method of reactivation of herpes simplex virus to examine the stimulation of tissue-resident T cells during secondary challenge. The results revealed that memory CD8 + T cell responses can be initiated within peripheral tissues through a tripartite interaction that includes CD4 + T cells and recruited dendritic cells. These findings lend evidence for the existence of a sophisticated T cell response mechanism in extra-lymphoid tissues that can act to control localized infection.

Selective suicide of cross-presenting CD8 ⁺ dendritic cells by cytochrome c injection shows functional heterogeneity within this subse

Publisher: Proceedings of the National Academy of Sciences

Date: 26-02-2008

DOI: 10.1073/PNAS.0712394105

Abstract: Cross-presentation as a fundamental pathway of activating CD8 + T cells has been well established. So far the application of this concept in vivo is limited, and the mechanisms that specialize CD8 + dendritic cells (DCs) for this task are not fully understood. Here we take advantage of the specific cytosolic export feature of cross-presenting DCs together with the property of cytosolic cytochrome c (cyt c ) in initiating Apaf-1-dependent apoptosis selectively in cross-presenting DCs. A single i.v. injection of cyt c in B6 mice produced a 2- to 3-fold reduction in splenic CD8 + DCs but not in Apaf-1-deficient mice. Functional studies both in vivo and in vitro showed that cyt c profoundly abrogated OVA-specific CD8 + T cell proliferation through its apoptosis-inducing effect on cross-presenting DCs. More importantly, in vivo injection of cyt c abolished the induction of cytotoxic T lymphocytes to exogenous antigen and reduced subsequent immunity to tumor challenge. In addition, only a proportion of CD8 + DCs that express abundant IL-12 and Toll-like receptor 3 were efficient cross-presenters. Our data support the hypothesis that cross-presentation in vivo requires cytosolic ersion of endocytosed proteins, conferring cross-presentation specialization to a proportion of CD8 + DCs. We propose that DCs incapable of such transfer, even within the CD8 + DC subset, are unable to cross-present. Our model opens an avenue to specifically target cross-presenting DCs in vivo for manipulating cytotoxic T lymphocyte responses toward infections, tumors, and transplants.

Extrafollicular CD4 T cell-derived IL-10 functions rapidly and transiently to support anti-Plasmodium humoral immunity

Publisher: Public Library of Science (PLoS)

Date: 02-02-2021

DOI: 10.1371/JOURNAL.PPAT.1009288

Abstract: Immunity against malaria depends on germinal center (GC)-derived antibody responses that are orchestrated by T follicular helper (TFH) cells. Emerging data show that the regulatory cytokine IL-10 plays an essential role in promoting GC B cell responses during both experimental malaria and virus infections. Here we investigated the cellular source and temporal role of IL-10, and whether IL-10 additionally signals to CD4 T-cells to support anti- Plasmodium humoral immunity. Distinct from reports of virus infection, we found that IL-10 was expressed by conventional, Foxp3-negative effector CD4 T cells and functioned in a B cell-intrinsic manner only during the first 96 hours of Plasmodium infection to support humoral immunity. The critical functions of IL-10 manifested only before the orchestration of GC responses and were primarily localized outside of B cell follicles. Mechanistically, our studies showed that the rapid and transient provision of IL-10 promoted B cell expression of anti-apoptotic factors, MHC class II, CD83, and cell-cell adhesion proteins that are essential for B cell survival and interaction with CD4 T cells. Together, our data reveal temporal features and mechanisms by which IL-10 critically supports humoral immunity during blood-stage Plasmodium infection, information that may be useful for developing new strategies designed to lessen the burden of malaria.

Up-regulation of LFA-1 allows liver-resident memory T cells to patrol and remain in the hepatic sinusoids

Publisher: American Association for the Advancement of Science (AAAS)

Date: 31-03-2017

DOI: 10.1126/SCIIMMUNOL.AAJ1996

Abstract: LFA-1 expression allows liver-resident CD8 + T cells to patrol hepatic sinusoids yet remain in the liver.

Differential expression of pathogen-recognition molecules between dendritic cell subsets revealed by plasma membrane proteomic analysis

Publisher: Elsevier BV

Date: 05-2010

DOI: 10.1016/J.MOLIMM.2010.02.028

Abstract: Dendritic cells (DC) are comprised of several subsets with distinct functions, differing in their capacity to respond to pathogen products. To gain novel insights into their pathogen specificity, we compared the protein composition of the plasma membrane of CD8+ and CD8- DC, directly isolated from mouse spleens. Differences in protein expression were determined using semi-quantitative high-resolution mass spectrometry of label-free plasma membrane-enriched fractions. Our comparative proteomic analysis detected over 1500 proteins, revealing broad differences in expression of pathogen receptors, adhesion molecules and T-cell regulatory molecules. Many of these findings were validated using flow cytometry and Western Blot analysis of integral and luminal surface-associated membrane proteins. This analysis provides major advantages over genomic approaches as it directly measures protein expression at a particular location. Our study highlights the ersity of surface protein expression amongst components of the DC network.

No driving without a license

Publisher: Springer Science and Business Media LLC

Date: 02-2005

DOI: 10.1038/NI0205-125

The unexpected contribution of conventional type 1 dendritic cells in driving antibody responses

Publisher: Wiley

Date: 19-12-2022

DOI: 10.1002/EJI.202149658

Abstract: Antibodies are hallmarks of most effective vaccines. For successful T‐dependent antibody responses, conventional dendritic cells (cDC) have been largely attributed the role of priming T cells. By contrast, follicular dendritic cells and macrophages have been seen as responsible for B cell activation, due to their strategic location within secondary lymphoid tissues and capacity to present native antigen to B cells. This review summarizes the mounting evidence that cDC can also present native antigen to B cells. cDC2 have been the main subset linked to humoral responses, based largely on their favorable location, capacity to prime CD4 + T cells, and ability to present native antigen to B cells. However, studies using strategies to deliver antigen to receptors on cDC1, reveal this subset can also contribute to naïve B cell activation, as well as T cell priming. cDC1 location within lymphoid tissues reveals their juxtaposition to B cell follicles, with ready access to B cells for presentation of native antigen. These findings support the view that both cDC1 and cDC2 are capable of initiating humoral responses provided antigen is captured by relevant surface receptors attuned to this process. Such understanding is fundamental for the development of innovative humoral vaccination approaches.

Migratory Dendritic Cells Transfer Antigen to a Lymph Node-Resident Dendritic Cell Population for Efficient CTL Priming

Publisher: Elsevier BV

Date: 07-2006

DOI: 10.1016/J.IMMUNI.2006.04.017

Abstract: Skin dendritic cells (DCs) are thought to act as key initiators of local T cell immunity. Here we show that after skin infection with herpes simplex virus (HSV), cytotoxic T lymphocyte (CTL) activation required MHC class I-restricted presentation by nonmigratory CD8(+) DCs rather than skin-derived DCs. Despite a lack of direct presentation by migratory DCs, blocking their egress from infected skin substantially inhibited class I-restricted presentation and HSV-specific CTL responses. These results support the argument for initial transport of antigen by migrating DCs, followed by its transfer to the lymphoid-resident DCs for presentation and CTL priming. Given that relatively robust CTL responses were seen with small numbers of skin-emigrant DCs, we propose that this inter-DC antigen transfer functions to lify presentation across a larger network of lymphoid-resident DCs for efficient T cell activation.

High expression of CD38 and MHC class II on CD8⁺ T cells during severe influenza disease reflects bystander activation and trogocytosis

Publisher: Wiley

Date: 2021

DOI: 10.1002/CTI2.1336

Abstract: Although co‐expression of CD38 and HLA‐DR reflects T‐cell activation during viral infections, high and prolonged CD38 + HLA‐DR + expression is associated with severe disease. To date, the mechanism underpinning expression of CD38 + HLA‐DR + is poorly understood. We used mouse models of influenza A/H9N2, A/H7N9 and A/H3N2 infection to investigate mechanisms underpinning CD38 + MHC‐II + phenotype on CD8 + T cells. To further understand MHC‐II trogocytosis on murine CD8 + T cells as well as the significance behind the scenario, we used adoptively transferred transgenic OT‐I CD8 + T cells and A/H3N2‐SIINKEKL infection. Analysis of influenza‐specific immunodominant D b NP 366 + CD8 + T‐cell responses showed that CD38 + MHC‐II + co‐expression was detected on both virus‐specific and bystander CD8 + T cells, with increased numbers of both CD38 + MHC‐II + CD8 + T‐cell populations observed in immune organs including the site of infection during severe viral challenge. OT‐I cells adoptively transferred into MHC‐II −/− mice had no MHC‐II after infection, suggesting that MHC‐II was acquired via trogocytosis. The detection of CD19 on CD38 + MHC‐II + OT‐I cells supports the proposition that MHC‐II was acquired by trogocytosis sourced from B cells. Co‐expression of CD38 + MHC‐II + on CD8 + T cells was needed for optimal recall following secondary infection. Overall, our study demonstrates that both virus‐specific and bystander CD38 + MHC‐II + CD8 + T cells are recruited to the site of infection during severe disease, and that MHC‐II presence occurs via trogocytosis from antigen‐presenting cells. Our findings highlight the importance of the CD38 + MHC‐II + phenotype for CD8 + T‐cell recall.

The liver contains distinct interconnected networks of CX3CR1⁺ macrophages, XCR1⁺ type 1 and CD301a⁺ type 2 conventional dendritic cel

Publisher: Wiley

Date: 19-06-2022

DOI: 10.1111/IMCB.12559

Abstract: Portal tracts are key intrahepatic structures where leukocytes accumulate during immune responses. They contain the blood inflow, which includes portal blood from the gut, and lymphatic and biliary outflow of the liver, and as such represent a key interface for potential pathogen entry to the liver. Myeloid cells residing in the interstitium of the portal tract might play an important role in the surveillance or prevention of pathogen dissemination however, the exact composition and localization of this population has not been explored fully. Our in‐depth characterization of portal tract myeloid cells revealed that in addition to T lymphocytes, portal tracts contain a heterogeneous population of MHCII high myeloid cells with potential antigen presenting cell (APC) function. These include a previously unreported subset of CSF1R‐dependent CX3CR1 + macrophages that phenotypically and morphologically resemble liver capsular macrophages, as well as the two main dendritic cell subsets (cDC1 and cDC2). These cells are not randomly distributed, but each subset forms interconnected networks intertwined with specific components of the portal tract. The CX3CR1 + cells were preferentially detected along the outer border of the portal tracts, and also in the portal interstitium adjacent to the portal vein, bile duct, lymphatic vessels and hepatic artery. cDC1s abounded along the lymphatic vessels, while cDC2s mostly surrounded the biliary tree. The specific distributions of these discrete subsets predict that they may serve distinct functions in this compartment. Overall, our findings suggest that portal tracts and their embedded cellular networks of myeloid cells form a distinctive lymphoid compartment in the liver that has the potential to orchestrate immune responses in this organ.

CD8+ and CD4+ T Cells Infiltrate into the Brain during Plasmodium berghei ANKA Infection and Form Long-Term Resident Memory

Publisher: The American Association of Immunologists

Date: 15-09-2021

DOI: 10.4049/JIMMUNOL.2000773

Abstract: In the Plasmodium berghei ANKA mouse model of malaria, accumulation of CD8+ T cells and infected RBCs in the brain promotes the development of experimental cerebral malaria (ECM). In this study, we used malaria-specific transgenic CD4+ and CD8+ T cells to track evolution of T cell immunity during the acute and memory phases of P. berghei ANKA infection. Using a combination of techniques, including intravital multiphoton and confocal microscopy and flow cytometric analysis, we showed that, shortly before onset of ECM, both CD4+ and CD8+ T cell populations exit the spleen and begin infiltrating the brain blood vessels. Although dominated by CD8+ T cells, a proportion of both T cell subsets enter the brain parenchyma, where they are largely associated with blood vessels. Intravital imaging shows these cells moving freely within the brain parenchyma. Near the onset of ECM, leakage of RBCs into areas of the brain can be seen, implicating severe damage. If mice are cured before ECM onset, brain infiltration by T cells still occurs, but ECM is prevented, allowing development of long-term resident memory T cell populations within the brain. This study shows that infiltration of malaria-specific T cells into the brain parenchyma is associated with cerebral immunopathology and the formation of brain-resident memory T cells. The consequences of these resident memory populations is unclear but raises concerns about pathology upon secondary infection.

CD8+ T Cell Activation Leads to Constitutive Formation of Liver Tissue-Resident Memory T Cells that Seed a Large and Flexible Niche in the Liver

Publisher: Elsevier BV

Date: 10-2018

DOI: 10.1016/J.CELREP.2018.08.094

Abstract: Liver tissue-resident memory T (Trm) cells migrate throughout the sinusoids and are capable of protecting against malaria sporozoite challenge. To gain an understanding of liver Trm cell development, we examined various conditions for their formation. Although liver Trm cells were found in naive mice, their presence was dictated by antigen specificity and required IL-15. Liver Trm cells also formed after adoptive transfer of in vitro-activated but not naive CD8

A Liver Capsular Network of Monocyte-Derived Macrophages Restricts Hepatic Dissemination of Intraperitoneal Bacteria by Neutrophil Recruitment

Publisher: Elsevier BV

Date: 08-2017

DOI: 10.1016/J.IMMUNI.2017.07.018

Abstract: The liver is positioned at the interface between two routes traversed by pathogens in disseminating infection. Whereas blood-borne pathogens are efficiently cleared in hepatic sinusoids by Kupffer cells (KCs), it is unknown how the liver prevents dissemination of peritoneal pathogens accessing its outer membrane. We report here that the hepatic capsule harbors a contiguous cellular network of liver-resident macrophages phenotypically distinct from KCs. These liver capsular macrophages (LCMs) were replenished in the steady state from blood monocytes, unlike KCs that are embryonically derived and self-renewing. LCM numbers increased after weaning in a microbiota-dependent process. LCMs sensed peritoneal bacteria and promoted neutrophil recruitment to the capsule, and their specific ablation resulted in decreased neutrophil recruitment and increased intrahepatic bacterial burden. Thus, the liver contains two separate and non-overlapping niches occupied by distinct resident macrophage populations mediating immunosurveillance at these two pathogen entry points to the liver.

Cross-presentation in viral immunity and self-tolerance

Publisher: Springer Science and Business Media LLC

Date: 11-2001

DOI: 10.1038/35100512

Abstract: T lymphocytes recognize peptide antigens presented by class I and class II molecules encoded by the major histocompatibility complex (MHC). Classical antigen-presentation studies showed that MHC class I molecules present peptides derived from proteins synthesized within the cell, whereas MHC class II molecules present exogenous proteins captured from the environment. Emerging evidence indicates, however, that dendritic cells have a specialized capacity to process exogenous antigens into the MHC class I pathway. This function, known as cross-presentation, provides the immune system with an important mechanism for generating immunity to viruses and tolerance to self.

Spatiotemporally Distinct Interactions with Dendritic Cell Subsets Facilitates CD4+ and CD8+ T Cell Activation to Localized Viral Infection

Publisher: Elsevier BV

Date: 09-2015

DOI: 10.1016/J.IMMUNI.2015.07.020

Abstract: The dynamics of when and where CD4(+) T cells provide help for CD8(+) T cell priming and which dendritic cells (DCs) activate CD4(+) T cells in vivo after localized infection are poorly understood. By using a cutaneous herpes simplex virus infection model combined with intravital 2-photon imaging of the draining lymph node (LN) to concurrently visualize pathogen-specific CD4(+) and CD8(+) T cells, we found that early priming of CD4(+) T cells involved clustering with migratory skin DCs. CD8(+) T cells did not interact with migratory DCs and their activation was delayed, requiring later clustering interactions with LN-resident XCR1(+) DCs. CD4(+) T cells interacted with these late CD8(+) T cell clusters on resident XCR1(+) DCs. Together, these data reveal asynchronous T cell activation by distinct DC subsets and highlight the key role of XCR1(+) DCs as the central platform for cytotoxic T lymphocyte activation and the delivery of CD4(+) T cell help.

The dendritic cell subtype-restricted C-type lectin Clec9A is a target for vaccine enhancement

Publisher: American Society of Hematology

Date: 15-10-2008

DOI: 10.1182/BLOOD-2008-05-155176

Abstract: A novel dendritic cell (DC)–restricted molecule, Clec9A, was identified by gene expression profiling of mouse DC subtypes. Based on sequence similarity, a human ortholog was identified. Clec9A encodes a type II membrane protein with a single extracellular C-type lectin domain. Both the mouse Clec9A and human CLEC9A were cloned and expressed, and monoclonal antibodies (mAbs) against each were generated. Surface staining revealed that Clec9A was selective for mouse DCs and was restricted to the CD8+ conventional DC and plasmacytoid DC subtypes. A subset of human blood DCs also expressed CLEC9A. A single injection of mice with a mAb against Clec9A, which targets antigens (Ags) to the DCs, produced a striking enhancement of antibody responses in the absence of added adjuvants or danger signals, even in mice lacking Toll-like receptor signaling pathways. Such targeting also enhanced CD4 and CD8 T-cell responses. Thus, Clec9A serves as a new marker to distinguish subtypes of both mouse and human DCs. Furthermore, targeting Ags to DCs with antibodies to Clec9A is a promising strategy to enhance the efficiency of vaccines, even in the absence of adjuvants.

Autoimmune regulator controls T cell help for pathogenetic autoantibody production in collagen‐induced arthritis

Publisher: Wiley

Date: 28-05-2009

DOI: 10.1002/ART.24501

Abstract: Autoimmune regulator (Aire) promotes the ectopic expression of tissue-restricted antigens in medullary thymic epithelial cells (mTECs), leading to negative selection of autoreactive T cells. This study was undertaken to determine whether loss of central tolerance renders Aire-deficient (Aire-/-) mice more susceptible to the induction of autoimmune arthritis. Medullary TECs were isolated from Aire-/- and wild-type C57BL/6 mice for gene expression analysis. Collagen-induced arthritis (CIA) was elicited by injection of chick type II collagen (CII) in adjuvant. Cellular and humoral immune responses to CII were evaluated. Chimeric mice were created by reconstituting lymphocyte-deficient mice with either Aire-/- or wild-type CD4 T cells and wild-type B cells. Wild-type, but not Aire-/-, mTECs expressed the CII gene Col2a1. Aire-/- mice developed more rapid and severe CIA, showing elevated serum anti-CII IgG levels, with earlier switching to arthritogenic IgG subclasses. No evidence was found of enhanced T cell responsiveness to CII in Aire-/- mice however, Aire-/- CD4 T cells were more efficient at stimulating wild-type B cells to produce anti-CII IgG following immunization of chimeric mice with CII. Our findings indicate that Aire-dependent expression of CII occurs in mTECs, implying that there is central tolerance to self antigens found in articular cartilage. Reduced central tolerance to CII in Aire-/- mice manifests as increased CD4 T cell help to B cells for cross-reactive autoantibody production and enhanced CIA. Aire and central tolerance help prevent cross-reactive autoimmune responses to CII initiated by environmental stimuli and limit spontaneous autoimmunity.

Blood-stage Plasmodium infection induces CD8⁺ T lymphocytes to parasite-expressed antigens, largely regulated by CD8α⁺ dendritic cells

Publisher: Proceedings of the National Academy of Sciences

Date: 23-09-2008

DOI: 10.1073/PNAS.0806727105

Abstract: Although CD8 + T cells do not contribute to protection against the blood stage of Plasmodium infection, there is mounting evidence that they are principal mediators of murine experimental cerebral malaria (ECM). At present, there is no direct evidence that the CD8 + T cells mediating ECM are parasite-specific or, for that matter, whether parasite-specific CD8 + T cells are generated in response to blood-stage infection. To resolve this and to define the cellular requirements for such priming, we generated transgenic P. berghei parasites expressing model T cell epitopes. This approach was necessary as MHC class I-restricted antigens to blood-stage infection have not been defined. Here, we show that blood-stage infection leads to parasite-specific CD8 + and CD4 + T cell responses. Furthermore, we show that P. berghei -expressed antigens are cross-presented by the CD8α + subset of dendritic cells (DC), and that this induces pathogen-specific cytotoxic T lymphocytes (CTL) capable of lysing cells presenting antigens expressed by blood-stage parasites. Finally, using three different experimental approaches, we provide evidence that CTL specific for parasite-expressed antigens contribute to ECM.

Adrenergic regulation of the vasculature impairs leukocyte interstitial migration and suppresses immune responses

Publisher: Elsevier BV

Date: 06-2021

DOI: 10.1016/J.IMMUNI.2021.03.025

Peptide-dependent recognition of H–2Kb by alloreactive cytotoxic T lymphocytes

Publisher: Springer Science and Business Media LLC

Date: 10-1989

DOI: 10.1038/341749A0

Abstract: Antigen-specific T lymphocytes appear to recognize foreign antigens in the form of peptide fragments presented within the antigen-binding groove of class I or class II molecules encoded by the major histocompatibility complex (MHC). Alloreactive T cells also show specificity for MHC molecules, and various reports suggest that residues of the MHC molecules constitute at least part of the ligand to which alloreactive T-cell receptors bind. The X-ray crystal structure of the human MHC class I molecule, HLA-A2, has provided evidence to strengthen the argument that MHC-bound self-peptide might also contribute to such recognition. We now provide direct evidence for this, showing that at least some alloreactive cytotoxic T lymphocyte clones recognize peptide fragments derived from cytoplasmic proteins. We reasoned that if self-peptides were involved in allorecognition, then the sequence of some of these peptides could vary between species, resulting in species-restricted distribution of the relevant ligand(s). Several alloreactive cytotoxic T lymphocyte clones specific for H-2Kb, expressed by the murine cell line EL4, did not lyse a human-cell transfectant expressing the H-2Kb molecule (Jurkat-Kb cells). However, these clones were able to lyse Jurkat-Kb cells sensitized by preincubation with an EL4 cytoplasmic extract cleaved by cyanogen bromide. The sensitizing activity from this extract was destroyed by protease and appeared to be due to a peptide consisting of 10 to 15 amino acids.

Peripheral deletion of autoreactive CD8⁺ T cells in transgenic mice expressing H‐2K^b in the liver

Publisher: Wiley

Date: 07-1995

DOI: 10.1002/EJI.1830250721

Abstract: The response of T cells specific for liver antigens was examined in transgenic mice expressing the allogeneic major histocompatibility complex class I molecule H-2Kb (Kb) under the control of the sheep metallothionein promoter (Met-Kb mice). To follow the fate of Kb-specific T cells, and to prevent any aberrant thymic expression of the Kb transgene, the mice were thymectomized, lethally irradiated, protected with bone marrow cells from transgenic mice expressing in their T cells a Kb-specific T cell receptor identifiable by a clonotypic antibody, and given syngeneic non-transgenic thymus grafts. Although Kb-specific CD8+ T cells were produced in the thymus grafts of these manipulated Met-Kb mice, only small numbers of such cells could be detected in the spleen and lymph nodes. The livers, however, showed signs of damage and were heavily infiltrated by actively iding CD8+ T cells. We provide strong evidence that the hepatocytes, not generally regarded as antigen-presenting cells, activated the Kb-specific CD8+ T cells and that these disappeared after a vigorous autoimmune response that resulted in deletion.

Life cycle, migration and antigen presenting functions of spleen and lymph node dendritic cells: Limitations of the Langerhans cells paradigm

Publisher: Elsevier BV

Date: 08-2005

DOI: 10.1016/J.SMIM.2005.05.015

Abstract: The phenotypic and functional studies carried out in recent years on dendritic cells (DC) purified from spleen and lymph nodes has revealed the existence of heterogeneous populations with distinct life cycles, migratory properties and antigen presenting functions. A major sub ision can be made between "tissue derived" DC that migrate to the lymph nodes from peripheral tissues, both in the steady state and in the course of infections, and "blood-derived" DC, which reside in the spleen and lymph nodes throughout their life cycle. These two groups of DC can be sub ided into smaller subsets. The tissue-derived and the blood-derived DC also show fundamental differences in maturational status and antigen presenting capabilities. In this review, we summarize the roles played by the different DC types in the steady state and during pathogen infections, relating those roles to maintenance of peripheral tolerance and the induction of immunity. We point out the caveats of assuming that the DC that collect antigens are the ones involved in their presentation, emphasizing the phenomenon of antigen transfer as an important component of the immune response.

Most lymphoid organ dendritic cell types are phenotypically and functionally immature

Publisher: American Society of Hematology

Date: 15-09-2003

DOI: 10.1182/BLOOD-2003-02-0513

Abstract: Dendritic cells (DCs) have been thought to follow a life history, typified by Langerhans cells (LCs), with 2 major developmental stages: an immature stage that captures antigens in the periphery and a mature stage that presents those antigens in the lymphoid organs. However, a systematic assessment of the maturity of lymphoid organ DCs has been lacking. We have analyzed the maturity of the DC types found in the steady state in the spleen, lymph nodes (LNs), and thymus. The DCs that migrate into the iliac, mesenteric, mediastinal, or subcutaneous LNs from peripheral tissues were mature and therefore could not process and present newly encountered antigens. However, all the other DC types were phenotypically and functionally immature: they expressed low levels of surface major histocompatibility complex class II (MHC II) and CD86, accumulated MHC II in their endosomes, and could present newly encountered antigens. These immature DCs could be induced to mature by culture in vitro or by inoculation of inflammatory stimuli in vivo. Therefore, the lymphoid organs contain a large cohort of immature DCs, most likely for the maintenance of peripheral tolerance, which can respond to infections reaching those organs and mature in situ.

A role for plasmacytoid dendritic cells in the rapid IL-18-dependent activation of NK cells following HSV-1 infection

Publisher: Wiley

Date: 19-04-2007

DOI: 10.1002/EJI.200636362

Migratory CD11b ⁺ conventional dendritic cells induce T follicular helper cell–dependent antibody responses

Publisher: American Association for the Advancement of Science (AAAS)

Date: 08-12-2017

DOI: 10.1126/SCIIMMUNOL.AAM9169

Abstract: Conventional DC2s are necessary and sufficient for priming T follicular helper cells.

Characterization of an Immediate Splenic Precursor of CD8+ Dendritic Cells Capable of Inducing Antiviral T Cell Responses

Publisher: The American Association of Immunologists

Date: 04-2009

DOI: 10.4049/JIMMUNOL.0802286

Abstract: Mouse spleens contain three major dendritic cell (DC) populations: plasmacytoid DC, conventional CD8+CD24+ DC (CD8+ DC), and conventional CD8−CD24− DC (CD8− DC). We have previously shown that CD8+ DC are the major cross-presenting subtype in vivo and are the main inducers of antiviral cytotoxic T lymphocyte responses. Here we show that after depletion of CD8+ DC, the only DC capable of viral Ag presentation was a small subset that expresses CD24 but not CD8. This CD8−CD24+ DC population is greatly expanded in mice treated with the DC growth factor FMS-like tyrosine kinase 3 ligand. The CD8−CD24+ DC represent an immediate precursor of CD8+ DC, as demonstrated by their expression pattern of characteristic markers of CD8+ DC, their capacity to cross-present in vitro, and their conversion into CD8+ DC upon adoptive transfer into recipient mice. Accordingly, the lifespan of transferred CD8−CD24+ DC in vivo was greatly enhanced as compared with terminally differentiated CD8+ DC. Moreover, in a vaccination protocol, CD8−CD24+ DC induced stronger T cell responses and accelerated viral clearance of HSV-1 compared with CD8+ DC. Our results demonstrate that the ability to cross-present first appears in an immediate precursor population of CD8+ DC that does not yet express CD8. The enhanced capacity of CD8−CD24+ DC to induce immune responses upon adoptive transfer makes them an attractive novel tool for DC-based immunotherapies.

Resident memory CD8 ⁺ T cells in the upper respiratory tract prevent pulmonary influenza virus infection

Publisher: American Association for the Advancement of Science (AAAS)

Date: 09-06-2017

DOI: 10.1126/SCIIMMUNOL.AAM6970

Abstract: Nasal tissue–resident memory T cells block influenza virus transmission to the lung, preventing severe pulmonary disease.

Too dangerous to ignore: self-tolerance and the control of ignorant autoreactive T cells

Publisher: Wiley

Date: 29-01-2008

DOI: 10.1038/SJ.ICB.7100161

Abstract: Self-reactive T cells often escape thymic negative selection and are released into the periphery. While many of these T cells are tolerized by peripheral deletion or anergy, a proportion persists in a naïve (or ignorant) state. Self-ignorant T cells are probably one of the greatest threats to the maintenance of self-tolerance, as inadvertent activation of these cells may provoke autoimmune pathology. Nevertheless, despite the presence of self-ignorant T cells within most in iduals, the majority of people fail to develop autoimmunity. The means by which self-ignorant T cells are silenced by the immune system remains a major issue within the tolerance field and it has received surprisingly little attention within the literature. In this review, we first summarize the factors that allow such cells to persist in a self-ignorant state, with a particular focus on the role of self-antigen dose. We next consider the conditions under which such self-reactive cells may become activated and speculate on how the immune system is able to prevent such cells from precipitating autoimmune disease.

Liver-Resident Memory CD8+ T Cells Form a Front-Line Defense against Malaria Liver-Stage Infection

Publisher: Elsevier BV

Date: 10-2019

DOI: 10.1016/J.IMMUNI.2019.09.019

Distinct APC subtypes drive spatially segregated CD4+ and CD8+ T-cell effector activity during skin infection with HSV-1

Publisher: Public Library of Science (PLoS)

Date: 14-08-2014

DOI: 10.1371/JOURNAL.PPAT.1004303

Targeting antigen to Clec9A primes follicular Th cell memory responses capable of robust recall

Publisher: The American Association of Immunologists

Date: 08-2015

DOI: 10.4049/JIMMUNOL.1500767

Abstract: Targeting Ags to dendritic cell (DC) surface receptors can induce a variety of responses depending on the DC type targeted, the receptor targeted, and the adjuvant used. Clec9A (DNGR-1), which is expressed by CD8+ DCs, has been shown to bind F-actin exposed on damaged cells. Targeting Ag to this receptor in mice and nonhuman primates induces strong humoral immunity even in the absence of adjuvant, a process seen for a few select DC receptors. In contrast with other receptors, however, targeting Clec9A induces long-lived, affinity-matured Ab responses that are associated with efficient CD4+ T cell responses shown to possess properties of follicular Th cells (TFH). In this article, we provide definitive evidence that Clec9A targeting promotes the development of TFH by showing that responding CD4 T cells express CXCR5, PD1, the TFH transcription factor Bcl6, and the cytokine IL-21, and that these cells localize to germinal centers. Furthermore, we extend studies from the model Ag OVA to the viral Ag glycoprotein D of HSV-1 and examine the capacity of primed TFH to form functional memory. We show that targeting glycoprotein D to Clec9A even in the absence of adjuvant induced long-lived memory CXCR5+ PD1hi CD4+ T cells that proliferated extensively upon secondary challenge and rapidly developed into effector TFH. This was associated with enhanced germinal center B cell responses and accelerated Ab production. Our study indicates that targeting Ags to Clec9A in the absence of adjuvant routinely generates TFH responses that form long-lived memory capable of robust secondary TFH responses.

Characterization of the ovalbumin-specific TCR transgenic line OT-I: MHC elements for positive and negative selection

Publisher: Wiley

Date: 04-2000

DOI: 10.1046/J.1440-1711.2000.00889.X

Abstract: The present report provides the first extensive characterization of the OT-I TCR transgenic line, which produces MHC class I-restricted, ovalbumin-specific, CD8+ T cells (OT-I cells). These cells are shown to be positively selected in vivo in H-2b C57BL/6 mice and in bm5 mice, which express the Kbm5 mutant molecule. In contrast, OT-I cells were not selected by mutant Kb molecules in bm1, bm3, bm8, bm10, bm11 or bm23 mice. Interestingly, however, when positive selection was examined in vitro in foetal thymic organ culture (FTOC), bm1 and bm8 were still poorly selective, but the bm3 haplotype now selected as efficiently as B6. The ability to select in vitro correlated with the capacity to present the ovalbumin (OVA) peptide to OT-I cells, as measured by induction of an OVA-specific proliferative response. These results suggest that a lower affinity TCR:MHC interaction may be necessary for positive selection in FTOC compared with selection in situ.

Development of a Novel CD4+TCR Transgenic Line That Reveals a Dominant Role for CD8+Dendritic Cells and CD40 Signaling in the Generation of Helper and CTL Responses to Blood-Stage Malaria

Publisher: The American Association of Immunologists

Date: 15-12-2017

DOI: 10.4049/JIMMUNOL.1700186

Abstract: We describe an MHC class II (I-Ab)–restricted TCR transgenic mouse line that produces CD4+ T cells specific for Plasmodium species. This line, termed PbT-II, was derived from a CD4+ T cell hybridoma generated to blood-stage Plasmodium berghei ANKA (PbA). PbT-II cells responded to all Plasmodium species and stages tested so far, including rodent (PbA, P. berghei NK65, Plasmodium chabaudi AS, and Plasmodium yoelii 17XNL) and human (Plasmodium falciparum) blood-stage parasites as well as irradiated PbA sporozoites. PbT-II cells can provide help for generation of Ab to P. chabaudi infection and can control this otherwise lethal infection in CD40L-deficient mice. PbT-II cells can also provide help for development of CD8+ T cell–mediated experimental cerebral malaria (ECM) during PbA infection. Using PbT-II CD4+ T cells and the previously described PbT-I CD8+ T cells, we determined the dendritic cell (DC) subsets responsible for immunity to PbA blood-stage infection. CD8+ DC (a subset of XCR1+ DC) were the major APC responsible for activation of both T cell subsets, although other DC also contributed to CD4+ T cell responses. Depletion of CD8+ DC at the beginning of infection prevented ECM development and impaired both Th1 and follicular Th cell responses in contrast, late depletion did not affect ECM. This study describes a novel and versatile tool for examining CD4+ T cell immunity during malaria and provides evidence that CD4+ T cell help, acting via CD40L signaling, can promote immunity or pathology to blood-stage malaria largely through Ag presentation by CD8+ DC.

Single-cell RNA-seq and computational analysis using temporal mixture modeling resolves T _H 1/T _FH fate bifurcation in malaria

Publisher: American Association for the Advancement of Science (AAAS)

Date: 31-03-2017

DOI: 10.1126/SCIIMMUNOL.AAL2192

Abstract: Computational modeling defines T helper cell differentiation toward multiple fates during experimental malaria.

Memory T cell subsets, migration patterns, and tissue residence

Publisher: Annual Reviews

Date: 21-03-2013

DOI: 10.1146/ANNUREV-IMMUNOL-032712-095954

Abstract: Tissues such as the skin and mucosae are frequently exposed to microbial pathogens. Infectious agents must be quickly and efficiently controlled by our immune system, but the low frequency of naive T cells specific for any one pathogen means dependence on primary responses initiated in draining lymph nodes, often allowing time for serious infection to develop. These responses imprint effectors with the capacity to home to infected tissues this process, combined with inflammatory signals, ensures the effective targeting of primary immunity. Upon vaccination or previous pathogen exposure, increased pathogen-specific T cell numbers together with altered migratory patterns of memory T cells can greatly improve immune efficacy, ensuring infections are prevented or at least remain subclinical. Until recently, memory T cell populations were considered to comprise central memory T cells (T CM ), which are restricted to the secondary lymphoid tissues and blood, and effector memory T cells (T EM ), which broadly migrate between peripheral tissues, the blood, and the spleen. Here we review evidence for these two memory populations, highlight a relatively new player, the tissue-resident memory T cell (T RM ), and emphasize the potential differences between the migratory patterns of CD4 + and CD8 + T cells. This new understanding raises important considerations for vaccine design and for the measurement of immune parameters critical to the control of infectious disease, autoimmunity, and cancer.

The NK cell granule protein NKG7 regulates cytotoxic granule exocytosis and inflammation

Publisher: Springer Science and Business Media LLC

Date: 24-08-2020

DOI: 10.1038/S41590-020-0758-6

Diminished secondary CTL response in draining lymph nodes on cutaneous challenge with herpes simplex virus

Publisher: Microbiology Society

Date: 02-2000

DOI: 10.1099/0022-1317-81-2-407

Abstract: We have shown that C57BL/6-derived CD8 + CTL specific for an immunodominant herpes simplex virus type 1 (HSV-1) glycoprotein B (gB) determinant express a highly conserved Vβ10/junctional sequence combination. This extreme T cell receptor β-chain bias can be used to track the activation of gB-specific CTL in lymph nodes draining the site of HSV-1 infection. In this report we have examined the accumulation of gB-specific CTL in the primary and secondary or recall CTL responses to HSV-1 infection. We found that gB-specific cytolytic activity present within popliteal lymph nodes draining HSV-infected foot-pads peaked at day 5 post-infection during the primary response. As found previously, this correlates with the accumulation of Vβ10 + CD8 + CTL in the activated T cell subset. Lymph node-derived cytotoxicity peaked between days 3 and 4 on secondary challenge with virus and, somewhat surprisingly, was considerably below that seen in the primary response. This reduced gB-specific cytolytic activity mirrored a near absence of Vβ10 + CD8 + T cell enrichment found within the draining lymph nodes during this recall response, consistent with the overall diminution of gB-specific CTL accumulation in this site. Finally, there was a second wave of biased accumulation of Vβ10 + CD8 + activated T cells within the popliteal lymph nodes well after the resolution of infection in both the primary and secondary responses. These results are discussed in terms of preferential activation of virus-specific memory T cells directly in infected tissues during a secondary CTL response at the expense of draining lymphoid organs.

Neutrophils are dispensable in the modulation of T cell immunity against cutaneous HSV-1 infection

Publisher: Springer Science and Business Media LLC

Date: 23-01-2017

DOI: 10.1038/SREP41091

Abstract: Neutrophils rapidly infiltrate sites of inflammation during peripheral infection or tissue injury. In addition to their well described roles as pro-inflammatory phagocytes responsible for pathogen clearance, recent studies have demonstrated a broader functional repertoire including mediating crosstalk between innate and adaptive arms of the immune system. Specifically, neutrophils have been proposed to mediate antigen transport to lymph nodes (LN) to modulate T cell priming and to influence T cell migration to infected tissues. Using a mouse model of cutaneous herpes simplex virus type 1 (HSV-1) infection we explored potential contributions of neutrophils toward anti-viral immunity. While a transient, early influx of neutrophils was triggered by dermal scarification, we did not detect migration of neutrophils from the skin to LN. Furthermore, despite recruitment of neutrophils into LN from the blood, priming and expansion of CD4 + and CD8 + T cells was unaffected following neutrophil depletion. Finally, we found that neutrophils were dispensable for the migration of effector T cells into infected skin. Our study suggests that the immunomodulatory roles of neutrophils toward adaptive immunity may be context-dependent, and are likely determined by the type of pathogen and anatomical site of infection.

Identification of a MHC I-restricted epitope of DsRed in C57BL/6 mice

Publisher: Elsevier BV

Date: 04-2013

DOI: 10.1016/J.MOLIMM.2012.10.003

Abstract: Fluorescent proteins can be used to visualize cells and their constituents by various imaging techniques. Adoptive transfer of T cells from C57Bl/6 (B6) mice that expressed DsRed.T3 under the actin promoter lead to frequent rejection of transferred cells. In short term in vivo cytotoxicity assays these mice showed detectable, but weak lysis of DsRed spleen cells but their responses could be boosted by re-challenge with DsRed spleen cells. To determine whether DsRed protein may contain an H-2(b) MHC I-restricted T cell epitope, B6 mice immune to DsRed spleen cells were examined for in vivo lysis of target cells coated with various DsRed-derived peptides selected by the SYFPEITHI epitope prediction program. This analysis identified one D(b)-restricted peptide sequence within DsRed (SSLQDGCFI) that acted as an epitope for B6 target lysis. Knowledge of this epitope could allow DsRed to be used as a model antigen in B6 mice and cautions against using this fluorochrome, as well as several others containing the immunogenic sequence, in adoptive transfer studies where rejection is not desirable.

Equivalent stimulation of naive and memory CD8 T cells by DNA vaccination: a dendritic cell-dependent process

Publisher: Wiley

Date: 27-01-2009

DOI: 10.1038/ICB.2008.105

Abstract: CD8 T-cell priming following DNA vaccination has been shown to confer protection against infections and tumors. These vaccines, however, have been disappointing in their ability to boost memory responses in prime-boost settings. We recently found that migratory dendritic cell (DC) subsets inefficiently stimulate memory CD8 T cells, raising the possibility that the poor boosting capacity of DNA encoded antigens might relate to their presentation by subsets of DCs that are only capable of efficiently stimulating naive T cells. Here, we show that DCs are required for T-cell priming in vivo following intradermal immunization with DNA-encoded antigens and that epidermal Langerhans cells are relatively unimportant. We then provide evidence that naive and memory CD8 T cells respond equally to DNA-encoded antigen. These findings show that immunization to DNA-encoded antigens is strongly DC-dependent and that the failure to boost memory T-cell immunity efficiently is not a consequence of a differential capacity of this form of antigen to stimulate naive or memory T cells.

Virus infection expands a biased subset of T cells that bind tetrameric class I peptide complexes.

Publisher: Wiley

Date: 06-2003

DOI: 10.1002/EJI.200323715

Abstract: We have used a TCR beta-chain transgenic mouse to examine the relationship between the ability of a T cell to bind soluble class I-peptide complexes and its response to antigenic stimulation in vivo. T cells from gBT-I.3beta TCR beta-chain transgenic mice preferentially carried TCR alpha-chains bearing the same Valpha2 V region as found in the parent receptor specific for an immunodominant HSV-1 gB-peptide. Furthermore, CD8(+) T cells from these mice bound K(b)-gB tetrameric complexes with relatively high frequency, and most of these cells contained a Valpha2 TCR alpha-chain. Detailed sequence analysis of the tetramer-binding peripheral T cells showed that this was a heterogenous population expressing TCR with only partial sequence similarity to the parent receptor, which took the form of preferential inclusion of the parental Jalpha16 element. Infection with HSV-1, however, selected a subset of tetramer-positive T cells. This was based on the emergence of a co-dominant Jalpha usage and selection of a restricted CDR3alpha length. Therefore, the ability to bind soluble MHC-peptide complexes does not always correlate with the ability of a T cell to respond to its cognate antigen after in vivo stimulation.

Cross‐presentation, dendritic cell subsets, and the generation of immunity to cellular antigens

Publisher: Wiley

Date: 05-05-2004

DOI: 10.1111/J.0105-2896.2004.00142.X

Effect of pre-existing cytotoxic T lymphocytes on therapeutic vaccines

Publisher: Wiley

Date: 02-2000

DOI: 10.1002/1521-4141(200002)30:2<671::AID-IMMU671>3.0.CO;2-H

High expression of CD38 and MHC class II on CD8⁺T cells during severe influenza disease reflects bystander activation and trogocytosis

Publisher: Cold Spring Harbor Laboratory

Date: 09-02-2021

DOI: 10.1101/2021.02.09.430410

Abstract: Although co-expression of CD38 and HLA-DR on CD8 + T cells reflects activation during influenza, SARS-CoV-2, Dengue, Ebola and HIV-1 viral infections, high and prolonged CD38 + HLA-DR + expression can be associated with severe and fatal disease outcomes. As the expression of CD38 + HLA-DR + is poorly understood, we used mouse models of influenza A/H7N9, A/H3N2 and A/H1N1 infection to investigate the mechanisms underpinning CD38 + MHC-II + phenotype on CD8 + T-cells. Our analysis of influenza-specific immunodominant D b NP 366 +CD8 + T-cell responses showed that CD38 + MHC-II + co-expression was detected on both virus-specific and bystander CD8 + T-cells, with increased numbers of both CD38 + MHC-II + CD8 + T-cell populations observed in the respiratory tract during severe infection. To understand the mechanisms underlying CD38 and MHC-II expression, we also used adoptively-transferred transgenic OT-I CD8 + T-cells recognising the ovalbumin-derived K b SIINFEKL epitope and A/H1N1-SIINKEKL infection. Strikingly, we found that OT-I cells adoptively-transferred into MHC-II −/− mice did not display MHC-II after influenza virus infection, suggesting that MHC-II was acquired via trogocytosis in wild-type mice. Additionally, detection of CD19 on CD38 + MHC II + OT-I cells further supports that MHC-II was acquired by trogocytosis, at least partially, sourced from B-cells. Our results also revealed that co-expression of CD38 + MHC II + on CD8 + T-cells was needed for the optimal recall ability following secondary viral challenge. Overall, our study provides evidence that both virus-specific and bystander CD38 + MHC-II + CD8 + T-cells are recruited to the site of infection during severe disease, and that MHC-II expression occurs via trogocytosis from antigen-presenting cells. Our findings also highlight the importance of the CD38 + MHC II + phenotype for CD8 + T-cell memory establishment and recall. Co-expression of CD38 and MHC-II on CD8 + T cells is recognized as a classical hallmark of activation during viral infections. High and prolonged CD38 + HLA-DR + expression, however, can be associated with severe disease outcomes and the mechanisms are unclear. Using our established influenza wild-type and transgenic mouse models, we determined how disease severity affected the activation of influenza-specific CD38 + MHC-II + CD8 + T cell responses in vivo and the antigenic determinants that drive their activation and expansion. Overall, our study provides evidence that both virus-specific and bystander CD38 + MHC-II + CD8 + T-cells are recruited to the site of infection during severe disease, and that MHC-II expression occurs, at least in part, via trogocytosis from antigen-presenting cells. Our findings also highlight the importance of the CD38 + MHC II + phenotype for CD8 + T-cell memory establishment and recall.

Kidney protection against autoreactive CD8(+) T cells distinct from immunoprivilege and sequestration

Publisher: Elsevier BV

Date: 08-2001

DOI: 10.1046/J.1523-1755.2001.060002664.X

Abstract: The kidney tubulointerstitium has been reported to be protected from T-cell--mediated damage by sequestration from the T-cell compartment. We examined the ability of autoreactive T cells to infiltrate the kidney in a transgenic mouse model. RIP-mOVA transgenic mice express the model autoantigen, membrane-bound ovalbumin (mOVA), in kidney proximal tubular cells and pancreatic beta cells. OVA-specific CD8(+) T cells (OT-I cells) were transferred into these recipient mice and their immune response against pancreas and kidney tissue was compared. When OVA-specific CD8(+) T cells (OT-I cells) were injected into RIP-mOVA mice, they were activated in the renal and pancreatic lymph nodes by cross-presentation. These in vivo-activated OT-I cells caused the destruction of pancreatic islets leading to autoimmune diabetes, but did not infiltrate the kidney. Neither CD95--CD95 ligand interactions, which have been proposed to induce apoptosis in T cells infiltrating immunologically privileged sites, nor CD30 signaling was responsible for the lack of kidney infiltration. When OT-I cells were activated in vitro prior to injection, they could infiltrate the kidney and caused acute renal failure when injected in high numbers. A mechanism distinct from previously described organ-specific protective mechanisms such as sequestration of antigen or CD95-mediated immunoprivilege contributes to the protection of the kidney tubulointerstitium from infiltration by autoreactive CD8(+) T cell.

Antibody responses initiated by Clec9A-bearing dendritic cells in normal and Batf3−/− mice

Publisher: Elsevier BV

Date: 02-2012

DOI: 10.1016/J.MOLIMM.2011.11.008

Abstract: Injection of antigens coupled to antibodies against the dendritic cell (DC) surface molecule Clec9A has been shown to produce strongly enhanced antibody responses even without co-administration of adjuvants, via antigen presentation by DC on MHC class II and consequent production of follicular helper T cells. A series of mutant mice were tested to determine the DC subtypes responsible for this MHC II presentation of targeted antigen, compared to presentation of antigen on MHC I. A new clec9A null mouse was developed these mice did not give enhanced antibody production, confirming the response was dependent on Clec9A-expressing DC. However targeting of antigen to Clec9A in batf3 null mice produced enhanced antibody responses despite the marked reduction in CD8(+) DC, the major Clec9A-expressing DC subtype. This was shown to be dependent on efficient MHC II presentation by minor Clec9A-expressing DC subtypes in the environment of the Batf3(-/-) mice, namely early cells of the CD8 DC lineage and the plasmacytoid-related CD8(+) DC subset, but not by plasmacytoid cells themselves. However in normal mice most MHC II presentation of the Clec9A-targeted antigen was by the major CD8(+) DC population, the DC also responsible for presentation on MHC I.

The clonal selection theory: 50 years since the revolution

Publisher: Springer Science and Business Media LLC

Date: 10-2007

DOI: 10.1038/NI1007-1019

Cutting edge: priming of CD8 T cell immunity to herpes simplex virus type 1 requires cognate TLR3 expression in vivo

Publisher: The American Association of Immunologists

Date: 03-2010

DOI: 10.4049/JIMMUNOL.0903013

Abstract: Despite its potential for involvement in viral immunity, little evidence links TLR3 to adaptive antiviral responses. Here we show that TLR3 is required for the generation of CD8 T cell immunity to HSV-1. The magnitude of the gB-specific CD8 T cell response after flank infection by HSV-1 was significantly reduced in mice lacking TIR domain-containing adaptor-inducing IFN-β or TLR3, but not MyD88. Impaired CTL induction was evident in chimeric mice lacking TLR3 in bone marrow (BM)-derived cells. Among the dendritic cell subsets, TLR3 was expressed by CD8α+ dendritic cells, known to be involved in priming HSV-1–specific CD8 T cells. Use of mixed BM chimeras revealed that TLR3 and the MHC class I-restriction element must be expressed by the same BM-derived cell for effective priming. These data imply that a cognate linkage between TLR3 and MHC class I is required for efficient CTL priming to HSV-1.

Inhibition of naive class I-restricted T cells by altered peptide ligands

Publisher: Wiley

Date: 08-1999

DOI: 10.1046/J.1440-1711.1999.00828.X

Abstract: Amino acid variants of an antigenic peptide or altered peptide ligands have previously been investigated with CD4+ and CD8+ T cells. However, for CD8+ T cells, only clones (which are continually restimulated in vitro) have been assessed. Using TCR transgenic mice specific for a class I Kb-restricted OVA peptide (OVAp OT-I mice) as a source of naïve CD8+ T cells, single amino acid variants of the OVAp were analysed in vitro for their ability to antagonize the proliferative and cytotoxic function of naïve OT-I cells. Peptides with substitutions at TCR contact residues were found to be the most potent antagonists of OT-I cell function. Those peptides that inhibited activation of cells to proliferate also inhibited activation of cells to become killers. Inhibition was inversely correlated with interferon (IFN)-gamma production. It was found that levels of antagonist peptide required for inhibition were higher than that described for T cell clones, presumably due to affinity differences.

Plasmodium berghei Hsp90 contains a natural immunogenic I-Ab-restricted antigen common to rodent and human Plasmodium species

Publisher: Elsevier BV

Date: 2021

DOI: 10.1016/J.CRIMMU.2021.06.002

Hemozoin-mediated inflammasome activation limits long-lived anti-malarial immunity.

Publisher: Elsevier BV

Date: 08-2021

DOI: 10.1016/J.CELREP.2021.109586

Chemokine receptor-dependent control of skin tissue-resident memory T Cell formation

Publisher: The American Association of Immunologists

Date: 10-2017

DOI: 10.4049/JIMMUNOL.1700571

Abstract: Infection or inflammation of the skin recruits effector CD8+ T cells that enter the epidermis and form populations of long-lived tissue-resident memory T (TRM) cells. These skin TRM cells migrate within the constrained epidermal environment by extending multiple dynamic dendritic projections and squeezing between keratinocytes to survey the tissue for pathogens. In this study, we examined the signals required for this distinctive mode of T cell migration by inhibiting key cytoskeletal components and performing intravital two-photon microscopy to visualize TRM cell behavior. We found that TRM cell motility and dendrite formation required an intact actomyosin cytoskeleton and the Rho-associated coiled-coil containing kinases. We also identified an essential role for microtubules for maintaining skin TRM cell shape and cellular integrity. We reveal a role for pertussis toxin–sensitive signaling for TRM cell dendritic morphology and migration that is independent of CXCR3 or CXCR6, or the skin-selective chemokine receptors CCR10 and CCR8. However, we found that CXCR6 and CCR10 expression by CD8+ T cells was required for the optimal formation of memory T cell populations, in particular TRM cell populations in the skin.

Different patterns of peripheral migration by memory CD4+ and CD8+ T cells

Publisher: Springer Science and Business Media LLC

Date: 14-08-2011

DOI: 10.1038/NATURE10339

Abstract: Infections localized to peripheral tissues such as the skin result in the priming of T-cell responses that act to control pathogens. Activated T cells undergo migrational imprinting within the draining lymph nodes, resulting in memory T cells that provide local and systemic protection. Combinations of migrating and resident memory T cells have been implicated in long-term peripheral immunity, especially at the surfaces that form pathogen entry points into the body. However, T-cell immunity consists of separate CD4(+) helper T cells and CD8(+) killer T cells, with distinct effector and memory programming requirements. Whether these subsets also differ in their ability to form a migrating pool involved in peripheral immunosurveillance or a separate resident population responsible for local infection control has not been explored. Here, using mice, we show key differences in the migration and tissue localization of memory CD4(+) and CD8(+) T cells following infection of the skin by herpes simplex virus. On resolution of infection, the skin contained two distinct virus-specific memory subsets a slow-moving population of sequestered CD8(+) T cells that were resident in the epidermis and confined largely to the original site of infection, and a dynamic population of CD4(+) T cells that trafficked rapidly through the dermis as part of a wider recirculation pattern. Unique homing-molecule expression by recirculating CD4(+) T effector-memory cells mirrored their preferential skin-migratory capacity. Overall, these results identify a complexity in memory T-cell migration, illuminating previously unappreciated differences between the CD4(+) and CD8(+) subsets.

Gamma interferon-independent effects of interleukin-12 on immunity to Salmonella enterica serovar typhimurium

Publisher: American Society for Microbiology

Date: 12-2007

DOI: 10.1128/IAI.00971-07

Abstract: Interleukin-12 (IL-12) and IL-18 are both central to the induction of gamma interferon (IFN-γ), and various roles for IL-12 and IL-18 in control of intracellular microbial infections have been demonstrated. We used IL-12p40 −/− and IL-18 −/− mice to further investigate the role of IL-12 and IL-18 in control of Salmonella enterica serovar Typhimurium. While C57BL/6 and IL-18 −/− mice were able to resolve attenuated S. enterica serovar Typhimurium infections, the IL-12p40 −/− mice succumbed to a high bacterial burden after 60 days. Using ovalbumin (OVA)-specific T-cell receptor transgenic T cells (OT-II cells), we demonstrated that following oral infection with recombinant S. enterica serovar Typhimurium expressing OVA, the OT-II cells proliferated in the mesenteric lymph nodes of C57BL/6 and IL-18 −/− mice but not in IL-12p40 −/− mice. In addition, we demonstrated by flow cytometry that equivalent or increased numbers of T cells produced IFN-γ in IL-12p40 −/− mice compared with the numbers of T cells that produced IFN-γ in C57BL/6 and IL-18 −/− mice. Finally, we demonstrated that removal of macrophages from S. enterica serovar Typhimurium-infected C57BL/6 and IL-12p40 −/− mice did not affect the bacterial load, suggesting that impaired control of S. enterica serovar Typhimurium infection in the absence of IL-12p40 is not due to reduced macrophage bactericidal activities, while IL-18 −/− mice did rely on the presence of macrophages for control of the infection. Our results suggest that IL-12p40, but not IL-18, is critical to resolution of infections with attenuated S. enterica serovar Typhimurium and that especially the effects of IL-12p40 on proliferative responses of CD4 + T cells, but not the ability of these cells to produce IFN-γ, are important in the resolution of infection by this intracellular bacterial pathogen.

Systemic activation of dendritic cells by Toll-like receptor ligands or malaria infection impairs cross-presentation and antiviral immunity

Publisher: Springer Science and Business Media LLC

Date: 15-01-2006

DOI: 10.1038/NI1300

Abstract: The mechanisms responsible for the immunosuppression associated with sepsis or some chronic blood infections remain poorly understood. Here we show that infection with a malaria parasite (Plasmodium berghei) or simple systemic exposure to bacterial or viral Toll-like receptor ligands inhibited cross-priming. Reduced cross-priming was a consequence of downregulation of cross-presentation by activated dendritic cells due to systemic activation that did not otherwise globally inhibit T cell proliferation. Although activated dendritic cells retained their capacity to present viral antigens via the endogenous major histocompatibility complex class I processing pathway, antiviral responses were greatly impaired in mice exposed to Toll-like receptor ligands. This is consistent with a key function for cross-presentation in antiviral immunity and helps explain the immunosuppressive effects of systemic infection. Moreover, inhibition of cross-presentation was overcome by injection of dendritic cells bearing antigen, which provides a new strategy for generating immunity during immunosuppressive blood infections.

SOCS-1 regulates IL-15-driven homeostatic proliferation of antigen-naive CD8 T cells, limiting their autoimmune potential

Publisher: Rockefeller University Press

Date: 10-10-2005

DOI: 10.1084/JEM.20050003

Abstract: Mice that are deficient in suppressor of cytokine signaling–1 (SOCS-1) succumb to neonatal mortality that is associated with extensive cellular infiltration of many tissues. T cells seem to be necessary for disease, which can be alleviated largely by neutralizing interferon-γ. Examining T cell receptor (TCR) specificity shows that even monospecific T cells can mediate disease in SOCS-1–deficient mice, although disease onset is substantially faster with a polyclonal T cell repertoire. A major phenotype of SOCS-1−/− mice is the accumulation of CD44highCD8+ peripheral T cells. We show that SOCS-1–deficient CD8, but not CD4, T cells proliferate when transferred into normal (T cell–sufficient) mice, and that this is dependent on two signals: interleukin (IL)-15 and self-ligands that are usually only capable of stimulating homeostatic expansion in T cell–deficient mice. Our findings reveal that SOCS-1 normally down-regulates the capacity of IL-15 to drive activation and proliferation of naive CD8 T cells receiving TCR survival signals from self-ligands. We show that such dysregulated proliferation impairs the deletion of a highly autoreactive subset of CD8 T cells, and increases their potential for autoimmunity. Therefore, impaired deletion of highly autoreactive CD8 T cells, together with uncontrolled activation of naive CD8 T cells by homeostatic survival ligands, may provide a basis for the T cell–mediated disease of SOCS-1−/− mice.

Expression of two T cell receptor α chains on the surface of normal murine T cells

Publisher: Wiley

Date: 06-1995

DOI: 10.1002/EJI.1830250622

Abstract: We have previously reported that a subset of T cells in T cell receptor (TCR)-transgenic mice may express two different alpha chains on their surface. The expression of two functional alpha chains has also been demonstrated for human peripheral blood T cells. In this report, we show that a proportion of normal murine lymph node T cells express two functional alpha chains on their surface. The extrapolated frequency of these cells present in the normal repertoire ranges from 7-21%, with an average of 15%. Our analysis of a small number of antigen-specific T cell clones suggests that the frequency of antigen-responsive cells expressing two surface alpha chains is relatively low. This raises the possibility that dual alpha chain T cells may have a selective disadvantage in responding to specific antigen.

Skin CD4(+) memory T cells exhibit combined cluster-mediated retention and equilibration with the circulation

Publisher: Springer Science and Business Media LLC

Date: 10-05-2016

DOI: 10.1038/NCOMMS11514

Abstract: Although memory T cells within barrier tissues can persist as permanent residents, at least some exchange with blood. The extent to which this occurs is unclear. Here we show that memory CD4 + T cells in mouse skin are in equilibrium with the circulation at steady state. These cells are dispersed throughout the inter-follicular regions of the dermis and form clusters with antigen presenting cells around hair follicles. After infection or administration of a contact sensitizing agent, there is a sustained increase in skin CD4 + T-cell content, which is confined to the clusters, with a concomitant CCL5-dependent increase in CD4 + T-cell recruitment. Skin CCL5 is derived from CD11b + cells and CD8 + T cells, with the elimination of the latter decreasing CD4 + T-cell numbers. These results reveal a complex pattern of tissue-retention and equilibration for CD4 + memory T cells in skin, which is altered by infection and inflammation history.

RNF41 regulates the damage recognition receptor Clec9A and antigen cross-presentation in mouse dendritic cells

Publisher: eLife Sciences Publications, Ltd

Date: 02-12-2020

DOI: 10.7554/ELIFE.63452

Abstract: The dendritic cell receptor Clec9A facilitates processing of dead cell-derived antigens for cross-presentation and the induction of effective CD8 + T cell immune responses. Here, we show that this process is regulated by E3 ubiquitin ligase RNF41 and define a new ubiquitin-mediated mechanism for regulation of Clec9A, reflecting the unique properties of Clec9A as a receptor specialized for delivery of antigens for cross-presentation. We reveal RNF41 is a negative regulator of Clec9A and the cross-presentation of dead cell-derived antigens by mouse dendritic cells. Intriguingly, RNF41 regulates the downstream fate of Clec9A by directly binding and ubiquitinating the extracellular domains of Clec9A. At steady-state, RNF41 ubiquitination of Clec9A facilitates interactions with ER-associated proteins and degradation machinery to control Clec9A levels. However, Clec9A interactions are altered following dead cell uptake to favor antigen presentation. These findings provide important insights into antigen cross-presentation and have implications for development of approaches to modulate immune responses.

Antibodies targeting Clec9A promote strong humoral immunity without adjuvant in mice and non-human primates

Publisher: Wiley

Date: 14-01-2015

DOI: 10.1002/EJI.201445127

Abstract: Targeting antigens to dendritic cell (DC) surface receptors using antibodies has been successfully used to generate strong immune responses and is currently in clinical trials for cancer immunotherapy. Whilst cancer immunotherapy focuses on the induction of CD8(+) T-cell responses, many successful vaccines to pathogens or their toxins utilize humoral immunity as the primary effector mechanism. Universally, these approaches have used adjuvants or pathogen material that augment humoral responses. However, adjuvants are associated with safety issues. One approach, successfully used in the mouse, to generate strong humoral responses in the absence of adjuvant is to target antigen to Clec9A, also known as DNGR-1, a receptor on CD8α(+) DCs. Here, we address two issues relating to clinical application. First, we address the issue of variable adjuvant-dependence for different antibodies targeting mouse Clec9A. We show that multiple sites on Clec9A can be successfully targeted, but that strong in vivo binding and provision of suitable helper T cell determinants was essential for efficacy. Second, we show that induction of humoral immunity to CLEC9A-targeted antigens is extremely effective in nonhuman primates, in an adjuvant-free setting. Our findings support extending this vaccination approach to humans and offer important insights into targeting design.

Dendritic cell preactivation impairs MHC class II presentation of vaccines and endogenous viral antigens.

Publisher: Proceedings of the National Academy of Sciences

Date: 06-11-2007

DOI: 10.1073/PNAS.0708622104

Abstract: When dendritic cells (DCs) encounter signals associated with infection or inflammation, they become activated and undergo maturation. Mature DCs are very efficient at presenting antigens captured in association with their activating signal but fail to present subsequently encountered antigens, at least in vitro . Such impairment of MHC class II (MHC II) antigen presentation has generally been thought to be a consequence of down-regulation of endocytosis, so it might be expected that antigens synthesized by the DCs themselves (for instance, viral antigens) would still be presented by mature DCs. Here, we show that DCs matured in vivo could still capture and process soluble antigens, but were unable to present peptides derived from these antigens. Furthermore, presentation of viral antigens synthesized by the DCs themselves was also severely impaired. Indeed, i.v. injection of pathogen mimics, which caused systemic DC activation in vivo , impaired the induction of CD4 T cell responses against subsequently encountered protein antigens. This immunosuppressed state could be reversed by adoptive transfer of DCs loaded exogenously with antigens, demonstrating that impairment of CD4 T cell responses was due to lack of antigen presentation rather than to overt suppression of T cell activation. The biochemical mechanism underlying this phenomenon was the down-regulation of MHC II–peptide complex formation that accompanied DC maturation. These observations have important implications for the design of prophylactic and therapeutic DC vaccines and contribute to the understanding of the mechanisms causing immunosuppression during systemic blood infections.

Elucidating the Motif for CpG Oligonucleotide Binding to the Dendritic Cell Receptor DEC-205 Leads to Improved Adjuvants for Liver-Resident Memory

Publisher: The American Association of Immunologists

Date: 10-2021

DOI: 10.4049/JIMMUNOL.2001153

Abstract: DEC-205 is a cell-surface receptor that transports bound ligands into the endocytic pathway for degradation or release within lysosomal endosomes. This receptor has been reported to bind a number of ligands, including keratin, and some classes of CpG oligodeoxynucleotides (ODN). In this study, we explore in detail the requirements for binding ODNs, revealing that DEC-205 efficiently binds single-stranded, phosphorothioated ODN of ≥14 bases, with preference for the DNA base thymidine, but with no requirement for a CpG motif. DEC-205 fails to bind double-stranded phosphodiester ODN, and thus does not bind the natural type of DNA found in mammals. The ODN binding preferences of DEC-205 result in strong binding of B class ODN, moderate binding to C class ODN, minimal binding to P class ODN, and no binding to A class ODN. Consistent with DEC-205 binding capacity, induction of serum IL-12p70 or activation of B cells by each class of ODN correlated with DEC-205 dependence in mice. Thus, the greater the DEC-205 binding capacity, the greater the dependence on DEC-205 for optimal responses. Finally, by covalently linking a B class ODN that efficiently binds DEC-205, to a P class ODN that shows poor binding, we improved DEC-205 binding and increased adjuvancy of the hybrid ODN. The hybrid ODN efficiently enhanced induction of effector CD8 T cells in a DEC-205–dependent manner. Furthermore, the hybrid ODN induced robust memory responses, and was particularly effective at promoting the development of liver tissue–resident memory T cells.

Epidermal viral immunity induced by CD8alpha+ dendritic cells but not by Langerhans cells

Publisher: American Association for the Advancement of Science (AAAS)

Date: 26-09-2003

DOI: 10.1126/SCIENCE.1087576

Abstract: The classical paradigm for dendritic cell function derives from the study of Langerhans cells, which predominate within skin epidermis. After an encounter with foreign agents, Langerhans cells are thought to migrate to draining lymph nodes, where they initiate T cell priming. Contrary to this, we show here that infection of murine epidermis by herpes simplex virus did not result in the priming of virus-specific cytotoxic T lymphocytes by Langerhans cells. Rather, the priming response required a distinct CD8α + dendritic cell subset. Thus, the traditional view of Langerhans cells in epidermal immunity needs to be revisited to accommodate a requirement for other dendritic cells in this response.

Signalling through CD30 protects against autoimmune diabetes mediated by CD8 T cells

Publisher: Springer Science and Business Media LLC

Date: 25-03-1999

DOI: 10.1038/18692

Abstract: Autoantigens found on pancreatic islets can move to draining lymph nodes, where they are able to cause the activation and consequent deletion of autoreactive T cells by a mechanism termed cross-tolerance. This deletion depends on signalling through CD95 (also known as Fas), a member of the superfamily of tumour-necrosis-factor receptors. Here we describe a new mechanism that protects against autoimmunity: this mechanism involves another member of this superfamily, CD30, whose function was largely unknown. CD30-deficient islet-specific CD8-positive T cells are roughly 6,000-fold more autoaggressive than wild-type cells, with the transfer of as few as 160 CD30-deficient T cells leading to the complete destruction of pancreatic islets and the rapid onset of diabetes. We show that, in the absence of CD30 signalling, cells activated but not yet deleted by the CD95-dependent cross-tolerance mechanism gain the ability to proliferate extensively upon secondary encounter with antigen on parenchymal tissues, such as the pancreatic islets. Thus, CD30 signalling limits the proliferative potential of autoreactive CD8 effector T cells and protects the body against autoimmunity.

Raster adaptive optics for video rate aberration correction and large FOV multiphoton imaging

Publisher: Optica Publishing Group

Date: 23-01-2020

DOI: 10.1364/BOE.377044

Abstract: Removal of complex aberrations at millisecond time scales over millimeters in distance in multiphoton laser scanning microscopy limits the total spatiotemporal imaging throughput for deep tissue imaging. Using a single low resolution deformable mirror and time multiplexing (TM) adaptive optics, we demonstrate video rate aberration correction (5 ms update rate for a single wavefront mask) for a complex heterogeneous distribution of refractive index differences through a depth of up to 1.1 mm and an extended imaging FOV of up to 0.8 mm, with up to 167% recovery of fluorescence intensity 335 µm from the center of the FOV. The proposed approach, termed raster adaptive optics (RAO), integrates image-based aberration retrieval and video rate removal of arbitrarily defined regions of dominant, spatially varied wavefronts. The extended FOV was achieved by demonstrating rapid recovery of up to 50 distinct wavefront masks at 500 ms update rates that increased imaging throughput by 2.3-fold. Because RAO only requires a single deformable mirror with image-based aberration retrieval, it can be directly implemented on a standard laser scanning multiphoton microscope.

SOCS1: a potent and multifaceted regulator of cytokines and cell-mediated inflammation

Publisher: Wiley

Date: 14-12-2006

DOI: 10.1111/J.1399-0039.2005.00532.X

Abstract: Suppressor of cytokine signalling-1 (SOCS1), as the name implies, is a protein that functions as a negative regulator of cytokine signalling. Initially characterized for its ability to inhibit JAK phosphorylation and function, SOCS1 also targets proteins for degradation by the proteosome machinery. The expression of SOCS1 can be regulated at the transcription, translation and protein level. Despite the broad spectrum of cytokines that can induce SOCS1 expression and/or be inhibited by SOCS1 in vitro, the use of genetically modified mice has revealed a more specific role for SOCS1 in vivo including a critical role in the regulation of IFNgamma signalling. In addition, SOCS1 has a complex role in T cell activation, and studies have revealed significant roles for SOCS1 in the regulation of IL-4, IL-12 and IL-15 in vivo. Interestingly, SOCS1 action is not limited to the regulation of the classical JAK/STAT-signalling pathway, because SOCS1 also inhibits cytokines like insulin and toll-like receptor signal transduction, neither of which activates the JAK/STAT pathway. Evidence is emerging for a role for aberrant SOCS1 expression in human disease, particularly in a number of malignancies.

The skin-resident and migratory immune system in steady state and memory: innate lymphocytes, dendritic cells and T cells

Publisher: Springer Science and Business Media LLC

Date: 18-09-2013

DOI: 10.1038/NI.2680

Abstract: The skin is a highly complex organ interspersed with a variety of smaller organ-like structures and a plethora of cell types that together perform essential functions such as physical sensing, temperature control, barrier maintenance and immunity. In this Review, we outline many of the innate and adaptive immune cell types associated with the skin, focusing on the steady state in mice and men, and include a broad update of dendritic cell function and T cell surveillance.

A local role for CD103+ dendritic cells in atherosclerosis

Publisher: Elsevier BV

Date: 11-2011

DOI: 10.1016/J.IMMUNI.2011.11.005

Abstract: In this issue of Immunity, Choi et al. (2011) analyzed the cellular composition of aortic vessels in normal and atherosclerotic mice, revealing the presence of conventional CD103(+) DCs with a potentially protective influence on atherosclerosis.

Generic construction of single component particles that elicit humoural and cellular immune responses without the need for adjuvants

Publisher: Elsevier BV

Date: 12-2008

DOI: 10.1016/J.VACCINE.2008.09.087

Abstract: Insoluble, pure protein particles could be advantageous as single-entity vaccines or as carriers for small peptide epitopes. Dense gas anti-solvent precipitation was employed to produce pure protein particles which were found to be insoluble in water. As particulate and multimerized antigens are more immunogenic and hence more advantageous for vaccination, particles were produced via this method using ovalbumin as a model antigen. The particles produced had a mean diameter of approximately 300nm, and remained as discrete particles at low pH. At neutral pH or in the presence of electrolyte, the particles exhibited predictable flocculation behaviour to produce aggregates 1-5microm in diameter. Immunisation of mice with these flocculates elicited specific ovalbumin antibody production, T-cell proliferation and a cytotoxic T-cell response, all in the absence of adjuvant. Thus, dense gas processing could be used as a generic method to produce pure protein particulate vaccines.

Bone marrow-derived cells expand memory CD8+ T cells in response to viral infections of the lung and skin

Publisher: Wiley

Date: 02-2006

DOI: 10.1002/EJI.200535432

Abstract: While naive CD8(+) T cells have been shown to require bone marrow-derived dendritic cells (DC) to initiate immunity, such a requirement for memory CD8(+) T cells has had limited assessment. By generating bone marrow chimeras that express the appropriate antigen-presenting molecules on either radiation-sensitive bone marrow-derived or radiation-resistant non-bone marrow-derived compartments, we showed that both primary and secondary immune responses to influenza virus infection of the lung were initiated in the draining LN. This required cells of bone marrow origin, most likely DC, for optimal expansion within the secondary lymphoid compartment. This was similarly the case with HSV-1 infection of the skin. As Langerhans cells are radioresistant, unlike other DC populations, these studies also demonstrate that the radiosensitive DC responsible for secondary expansion of HSV-specific memory are not Langerhans cells.

Outside looking in: the inner workings of the crosspresentation pathway within dendritic cells

Publisher: Elsevier BV

Date: 02-2007

DOI: 10.1016/J.IT.2006.12.008

Abstract: The entry of exogenous antigen into the MHC class I-restricted cross-presentation pathway can contribute to CD8(+) T cell tolerance and immunity, in particular to peripheral self-antigens or selected viruses and bacteria showing restricted tissue tropism. Dendritic cells are the key cross-presenting cells and, as such, they are thought to carry specialized machinery dedicated to this purpose. Two recent papers describe intracellular components tailored to the dendritic cell cross-presentation pathway.

Tissue destruction caused by cytotoxic T lymphocytes induces deletional tolerance

Publisher: Proceedings of the National Academy of Sciences

Date: 10-03-2009

DOI: 10.1073/PNAS.0810427106

Abstract: Autoimmune diseases tend to be chronic and progressive, but how these responses are sustained is not clear. One cell type that might contribute to autoimmunity is the cytotoxic T lymphocyte (CTL), which, as a consequence of causing tissue destruction and production of cytokines, could provide a sustained supply of antigen and inflammatory signals for dendritic cells to maintain immune stimulation. Here we examined whether such CTL-mediated tissue damage alone could provide antigen in the right context to recruit immune effectors and sustain autoimmunity. We show that while CTL-mediated tissue damage caused the release of self-antigens that stimulated the proliferation of naive autoreactive CD8 + T cells, such responses failed to precipitate disease and, instead, led to deletional tolerance. These findings indicate that despite the capacity of CTLs to produce inflammatory cytokines and to cause tissue damage, their responses are not sustaining, but instead favor induction of self-tolerance.

Initiation of autoimmune diabetes by developmentally regulated presentation of islet cell antigens in the pancreatic lymph nodes.

Publisher: Rockefeller University Press

Date: 18-01-1999

DOI: 10.1084/JEM.189.2.331

Abstract: Little is known about the events triggering lymphocyte invasion of the pancreatic islets in prelude to autoimmune diabetes. For ex le, where islet-reactive T cells first encounter antigen has not been identified. We addressed this issue using BDC2.5 T cell receptor transgenic mice, which express a receptor recognizing a natural islet beta cell antigen. In BDC2.5 animals, activated T cells were found only in the islets and the lymph nodes draining them, and there was a close temporal correlation between lymph node T cell activation and islet infiltration. When naive BDC2.5 T cells were transferred into nontransgenic recipients, proliferating cells were observed only in pancreatic lymph nodes, and this occurred significantly before insulitis was detectable. Surprisingly, proliferation was not seen in 10-day-old recipients. This age-dependent dichotomy was reproduced in a second transfer system based on an unrelated antigen artificially expressed on beta cells. We conclude that beta cell antigens are transported specifically to pancreatic lymph nodes, where they trigger reactive T cells to invade the islets. Systemic or extrapancreatic T cell priming, indicative of activation via molecular mimicry or superantigens, was not seen. Compromised presentation of beta cell antigens in the pancreatic lymph nodes of juvenile animals may be the root of a first “checkpoint” in diabetes progression.

Latent infection with herpes simplex virus is associated with ongoing CD8+ T-cell stimulation by parenchymal cells within sensory ganglia

Publisher: American Society for Microbiology

Date: 15-12-2005

DOI: 10.1128/JVI.79.23.14843-14851.2005

Abstract: CD8 + T-cell persistence can be seen in ganglia harboring latent herpes simplex virus (HSV) infection. While there is some evidence that these cells suppress virus reactivation, this view remains controversial. Given that maintenance of latency by CD8 + T cells would necessitate ongoing exposure to antigen within this site, we sought evidence for such chronic stimulation. Initial experiments showed infiltration by activated but not naïve CD8 + T cells into ganglia harboring latent HSV infection. While such infiltration was independent of T-cell specificity, once recruited, only virus-specific T cells expressed high levels of preformed granzyme B, a marker of ongoing activation. Moreover, bone marrow replacement chimeras showed that these elevated granzyme levels were totally dependent on presentation by parenchymal cells within the ganglia. Overall, this study argues that activated CD8 + T cells are nonspecifically recruited into latently infected ganglia, and in this site they are exposed to ongoing antigen stimulation, most likely by infected neuronal cells.

The cryo-EM structure of the endocytic receptor DEC-205

Publisher: Elsevier BV

Date: 2021

DOI: 10.1074/JBC.RA120.016451

University Of Melbourne

Location: Australia

View Organisation

Federation Fellowships - Grant ID: FF0776147

Start Date: 06-2008

End Date: 12-2013

Amount: $1,995,744.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE110100106

Start Date: 07-2011

End Date: 12-2012

Amount: $350,000.00

Funder: Australian Research Council

ARC Centres Of Excellence - Grant ID: CE140100011

Start Date: 06-2014

End Date: 03-2021

Amount: $27,999,996.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE140100070

Start Date: 2014

End Date: 12-2015

Amount: $650,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP190103691

Start Date: 2019

End Date: 12-2021

Amount: $580,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP0986522

Start Date: 08-2009

End Date: 08-2014

Amount: $829,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0989226

Start Date: 2009

End Date: 12-2009

Amount: $340,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP220103545

Start Date: 02-2022

End Date: 02-2026

Amount: $770,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP130102481

Start Date: 2013

End Date: 12-2015

Amount: $420,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE150100163

Start Date: 2015

End Date: 12-2016

Amount: $560,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE210100001

Start Date: 07-2021

End Date: 07-2022

Amount: $875,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE110100125

Start Date: 10-2011

End Date: 10-2012

Amount: $500,000.00

Funder: Australian Research Council