ORCID Profile
0000-0002-7443-0543
Current Organisation
University of Melbourne
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Cell Physiology | Biochemistry and Cell Biology | Cell Development, Proliferation and Death
Publisher: Elsevier BV
Date: 10-2004
Publisher: Informa UK Limited
Date: 07-05-2015
Publisher: Wiley
Date: 06-2013
Abstract: Vitamin A and its metabolite retinoic acid influence various aspects of immunity. Although the capacity of vitamin A to condition intestinal CD103(+) DCs to imprint tissue-specific homing programs onto activated lymphocytes is well documented, it is unclear whether vitamin A also regulates DC populations in other tissues. A study published in this issue of the European Journal of Immunology, Beijer et al. [Eur. J. Immunol. 2013. 43: 1608-1616] now demonstrates that vitamin A exerts profound effects on the subset composition of splenic DCs. By resolving that splenic ESAM(hi) CD11b(hi) DCs are preferentially responsive to regulation by vitamin A, these novel insights not only further support the notion that ESAM expression marks two distinct lineages of splenic CD11b(hi) DCs, but also provide an important extension to our understanding of how vitamin A influences the immune system.
Publisher: Elsevier BV
Date: 02-2009
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.
Publisher: Proceedings of the National Academy of Sciences
Date: 21-04-2009
Abstract: Antigen expressed as MHC Class I glycoprotein (pMHCI) complexes on dendritic cells is the primary driver of CD8 + T cell clonal expansion and differentiation. As we seek to define the molecular differences between acutely stimulated cytotoxic T lymphocyte (CTL) effectors and long-lived memory T cells, it is essential that we understand the duration of in vivo pMHCI persistence. Although infectious influenza A virus is readily cleared by mammalian hosts, that does not necessarily mean that all influenza antigen is totally eliminated. An exhaustive series of carefully controlled adoptive transfer experiments using 3 different carboxy fluorescein diacetate succinimidyl ester–labeled T cell receptor–transgenic CTL populations and a spectrum of genetically engineered and wild-type influenza A viruses provided no evidence for pMHCI persistence over the 30–60-d interval after virus challenge. Molecular profiles identified in antigen-specific T cells at this time may thus be considered to reflect established immunologic memory and not recent CTL activation from a persistent pMHCI pool.
Publisher: Cold Spring Harbor Laboratory
Date: 08-06-2023
DOI: 10.1101/2023.06.08.542671
Abstract: The presence of immune cells in non-lymphoid tissues throughout the body is vital in the fight against infections and cancer. Yet, a detailed map of immune cell distribution and interactions throughout the body is lacking. To address this gap, we harmonised and annotated 29 million cells across 12,981 single-cell RNA sequencing s les covering 45 anatomical sites to create a comprehensive compositional and communication map of the healthy immune system. This resource represents a 30-fold increase in cell count and a 10-fold increase in tissue coverage compared to the existing state-of-the-art. We used this resource to model compositional changes in the immune system with age and ersity across demographic groups and to investigate the impact of different technologies using a novel multilevel Bayesian model. Our analysis revealed patterns of progressive tissue-specific inflammation, loss of plasticity with age, and significant differences between ethnicities. This study represents a comprehensive healthy reference for precision medicine, immunology, infectious disease and cancer.
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.
Publisher: Public Library of Science (PLoS)
Date: 02-2016
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.
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.VIROL.2010.08.001
Abstract: Neutrophils are prominent in epidermal and dermal layers of human herpetic lesions and are rapidly recruited into the skin follow epidermal abrasion and infection of mice with herpes simplex virus type-1 (HSV-1). Herein, we demonstrate that early production of neutrophil-attracting chemokines KC/MIP-2 is associated with transient recruitment of neutrophils into the skin of HSV-1-infected mice in temporal association with the development of herpetic lesions. Treatment of HSV-1-infected mice with a Ly6G-specific mAb induced systemic neutropenia, but surprisingly did not alter virus replication or lesion development. In contrast, depletion of Gr-1(+) cells with mAb RB6-8C5 led to enhanced virus growth and lesion severity. Thus, while neutrophils are prominent in zosteriform lesions of HSV-1-infected mice, they do not appear to play a major role in controlling virus replication or lesion development and/or healing. In contrast, Gr-1(+) cells limit both virus replication and lesion development in the zosteriform model.
Publisher: Wiley
Date: 18-02-2016
Abstract: The immune system has the ability to specifically identify and eliminate tumors, but the underlying mechanisms responsible for this phenomenon are not fully understood. A study published in this issue of the European Journal of Immunology now provides new insights into this important problem. Joncker et al. [Eur. J. Immunol. 2016. 46: 609-618] show that the timely mobilization of tumor antigen-bearing dendritic cells (DCs) from the periphery to the lymph nodes is critical for effective antitumor T-cell immunity, and that DCs present tumor antigens much more efficiently when encountered in the skin rather than in the subcutaneous tissues.
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.
Publisher: The American Association of Immunologists
Date: 02-2019
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.
Publisher: Microbiology Society
Date: 09-06-2010
Abstract: In the absence of a viable 'knockout' mouse, researchers have relied extensively on monoclonal antibody (mAb) RB6-8C5 [anti-granulocyte receptor 1 (Gr-1)] to deplete neutrophils in murine models of inflammation and infection. Using an intranasal model of herpes simplex virus type 1 (HSV-1) infection, we demonstrate that mAb RB6-8C5 also binds to plasmacytoid dendritic cells, F4/80(+) macrophages/monocytes and CD8(+) T cells recovered from the airways of HSV-1-infected mice. In contrast, mAb 1A8 (anti-Ly6G) bound specifically to Ly6G(high) neutrophils. Following intranasal infection of C57BL/6 mice with HSV-1, few Ly6G(high) neutrophils were recruited to the airways and treatment of mice with purified mAb 1A8 induced systemic neutropenia, but did not alter virus replication or disease progression. In contrast, treatment of HSV-1-infected mice with mAb RB6-8C5 led to exacerbated virus replication, disease severity and mortality. These findings highlight the limitations associated with widespread use of antibody-mediated depletion of Gr-1(+) cells to define the role of neutrophils in vivo. Furthermore, we use mAb 1A8 to demonstrate that specific depletion of neutrophils does not modulate disease or alter virus replication following intranasal infection with HSV-1.
Publisher: American Society for Microbiology
Date: 12-2014
DOI: 10.1128/IAI.02192-14
Abstract: The rational design of vaccines requires an understanding of the contributions of in idual immune cell subsets to immunity. With this understanding, targeted vaccine delivery approaches and adjuvants can be developed to maximize vaccine efficiency and to minimize side effects (S. H. E. Kaufmann et al., Immunity 33:555–577, 2010 T. Ben-Yedidia and R. Arnon, Hum. Vaccines 1:95–101, 2005). We have addressed the contributions of different immune cell subsets and their ability to contribute to the control and clearance of the facultative intracellular pathogen Salmonella enterica serovar Typhimurium ( S . Typhimurium) in a murine model. Using a systematic and reproducible model of experimental attenuated S . Typhimurium infection, we show that distinct lymphocyte deficiencies lead to one of four different infection outcomes: clearance, chronic infection, early death, or late death. Our study demonstrates a high level of functional redundancy in the ability of different lymphocyte subsets to provide interferon gamma (IFN-γ), a critical cytokine in Salmonella immunity. Whereas early control of the infection was entirely dependent on IFN-γ but not on any particular lymphocyte subset, clearance of the infection critically required CD4 + T cells but appeared to be independent of IFN-γ. These data reinforce the idea of a bimodal immune response against Salmonella : an early T cell-independent but IFN-γ-dependent phase and a late T cell-dependent phase that may be IFN-γ independent.
Publisher: Elsevier
Date: 2016
Publisher: The American Association of Immunologists
Date: 03-2015
Abstract: Tissue-resident memory T cells provide local immune protection in barrier tissues, such as skin and mucosa. However, the molecular mechanisms controlling effector T cell retention and subsequent memory formation in those locations are not fully understood. In this study, we analyzed the role of CD69, an early leukocyte activation marker, in regulating effector T cell egress from peripheral tissues. We provide evidence that CD69 surface expression by skin-infiltrating CD8 T cells can be regulated at multiple levels, including local Ag stimulation and signaling through type I IFNRs, and it coincides with the transcriptional downregulation of the sphingosine-1-phosphate receptor S1P1. Importantly, we demonstrate that expression of CD69, by interfering with sphingosine-1-phosphate receptor function, is a critical determinant of prolonged T cell retention and local memory formation. Our results define an important step in the generation of long-lived adaptive immune memory at body surfaces.
Publisher: Wiley
Date: 07-01-2014
DOI: 10.1038/ICB.2013.102
Abstract: We have previously shown that the immunogenicity of protein antigens can be significantly enhanced if electrostatically associated with the Toll-like receptor-2 agonist-based lipopeptide R4Pam2Cys. The precise mechanisms and effectiveness of the cytotoxic T-lymphocyte (CTL)-mediated response facilitated by this agonist, however, have not been studied. Here we show that priming by dendritic cells (DCs) in the draining lymph nodes of animals vaccinated with antigen delivered using R4Pam2Cys results in significantly improved T-cell proliferation and induces their differentiation into polyfunctional effector CTLs characterised by granzyme B expression and the ability to secrete interferon-γ, interleukin-2 and tumor necrosis factor-α 7 days after vaccination. After 30 days, frequencies of antigen-specific CD62(low)CD127(high) (effector memory), CD62(high)CD127(high) (central memory) and CD43(low)CD27(high) CD8(+) T cells, a phenotype associated with strong recall responses against respiratory infections, are also increased compared with responses obtained with antigens formulated in the adjuvants Alum (alhydrogel) and CFA (complete Freund's adjuvant). The phenotypic changes observed in these mice vaccinated using R4Pam2Cys further correlated with their ability to recall specific T cells into the lung to mediate the reduction of pulmonary viral titres following challenge with a chimeric influenza virus containing the K(b)OVA257-264 epitope compared with animals vaccinated using Alum or CFA. The findings from this study not only demonstrate that better T-cell responses can be elicited using R4Pam2Cys compared with classically utilised adjuvants but also highlight the potential effectiveness of this lipopeptide-based adjuvant particularly against viral infections that require resolution through cell-mediated immunity.
Publisher: Elsevier BV
Date: 02-2011
DOI: 10.1016/J.COI.2010.11.001
Abstract: Effective viral immunity depends on the activation of T cells by professional antigen presenting cells, such as dendritic cells (DC). The remarkable heterogeneity of the DC network allows the immune system to respond specifically to various infection strategies by different viruses. As a consequence, DC-T cell interactions resulting in optimal virus-specific T cell priming are highly flexible and involve different types of DC. Further highlighting this complexity, recent lines of evidence suggest that presentation of viral antigen by DC is not only restricted to lymphoid organs, but instead also occurs at peripheral sites of infection. Here we discuss the multifaceted interactions between DC and T cells during peripheral virus infections in both lymphoid organs and the periphery.
Publisher: Wiley
Date: 17-04-2018
DOI: 10.1111/IMR.12650
Abstract: A large proportion of memory T cells disseminated throughout the body are non-recirculating cells whose maintenance and function is regulated by tissue-specific environmental cues. These sessile cells are referred to as tissue-resident memory T (T
Publisher: Public Library of Science (PLoS)
Date: 2014
Publisher: The American Association of Immunologists
Date: 04-2009
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.
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.
Publisher: Public Library of Science (PLoS)
Date: 14-05-2014
Publisher: Wiley
Date: 04-08-2011
Abstract: Resident CD8(+) DCs perform several functions, including cross-presenting antigen and rapidly engulfing the Gram-positive intracellular pathogen Listeria monocytogenes. Little is known about how these functions of CD8(+) DCs are modulated. Here, we show that granulocyte-macrophage CSF (GM-CSF), a cytokine that exists at low levels at steady state but is elevated during infection and inflammation, enhances cross-presentation and rapid uptake of L. monocytogenes by resident CD8(+) DCs. This previously unrecognized functional enhancement of CD8(+) DCs by GM-CSF was independent of promoting DC survival in vitro. Enhancement of these functions by GM-CSF was also marked by CD103 expression on CD8(+) DCs that was strongly regulated by GM-CSF. Our findings not only identify GM-CSF as a key molecule regulating CD8(+) DC function, but also as a factor responsible for functional heterogeneity of CD8(+) DCs that is at least substantially demarcated by CD103 expression.
Publisher: Elsevier BV
Date: 02-2007
DOI: 10.1016/J.PEPTIDES.2006.07.029
Abstract: Although it is broadly accepted that the immune system and the nervous system functionally interact with each other at various levels, many aspects of this crosstalk still remain unclear. One player in this interaction is neuropeptide Y (NPY), a sympathetic neurotransmitter, which has been demonstrated to regulate a broad variety of immune functions. In this review we will outline key findings on the effects NPY exerts on phagocytosis by neutrophils and monocytes/macrophages and its relevance to the elimination of invading pathogens. Furthermore, we will discuss the implications of these findings for antigen presentation by dendritic cells and the induction of adaptive immune responses.
Publisher: Elsevier BV
Date: 11-2008
DOI: 10.1016/J.REGPEP.2008.05.004
Abstract: Leptin, a hormone mainly generated by adipocytes, acts centrally in the hypothalamus to regulate body weight and energy expenditure. However, there is strong evidence that leptin is also involved in cell-mediated immunity and cytokine crosstalk. In the present study the effects of diet-induced obesity and central and peripheral leptin treatment on leukocyte subsets and cytokine production was investigated. Leptin was injected either intravenously (i.v.) or intracerebroventricularly (i.c.v.) in male endotoxaemic or vehicle-treated healthy LEW-rats. Numbers of blood leukocyte subsets were analysed by FACS and cytokines (TNF-alpha and IL-6) by ELISA. Results showed that peripheral rather than central leptin treatment was able to significantly increase numbers of granulocytes, NK cells and monocytes. Three-colour staining revealed that the increase of ED9(+) monocytes was most likely due to the mobilization of two distinct monocyte subsets, predominantly ED9(+)CD4(-)NKR-P1A(+) and ED9(+)CD4(+)NKR-P1A(+). ELISA analysis revealed significantly elevated TNF-alpha levels in obese animals compared to their lean littermates, while IL-6 failed to show notable changes. In conclusion, the data of the present study revealed that leptin application induces a nutrition- and application-site dependent increase of circulating NK cells, granulocytes and specific monocyte subsets.
Publisher: Public Library of Science (PLoS)
Date: 14-08-2014
Publisher: Wiley
Date: 03-2013
DOI: 10.1038/ICB.2012.85
Publisher: Springer Science and Business Media LLC
Date: 19-04-2016
DOI: 10.1038/NI.3432
Abstract: Lymphocytes are essential in innate and adaptive immunity. Recent insights suggest that some innate lymphocytes execute functions with adaptive characteristics, while adaptive lymphocytes can operate in ways reminiscent of innate cells. Rather than partitioning lymphocytes according to the type of effector function they execute, we propose that a relevant discrimination relates to the existence of conventional T cells in a naive state. The naive state can be seen as an actively repressed condition that supports T cell ersity and enables the flexible differentiation of effector cells in a manner that best addresses the antigenic challenge. We discuss these considerations in the context of the relative roles of innate lymphoid cells and antigen-experienced T cells in the immune system.
Publisher: American Physiological Society
Date: 06-2007
DOI: 10.1152/AJPLUNG.00273.2006
Abstract: The ovalbumin (OVA)-induced airway inflammation in rats is a commonly used model to explore the pathobiology of asthma. However, its susceptibility varies greatly between rat strains, and presently Brown Norway (BN) rats are preferentially used. Since recruitment of T cells to the lungs depends on the CD26 (dipeptidyl peptidase IV, DPPIV) expression, Fischer 344 strain (F344) rats are a highly relevant rat strain, in particular because CD26-deficient substrains are available. To establish a F344 rat model of asthma, we challenged F344 rats using different doses of aerosolized antigen (0%, 1%, 2.5%, 5%, and 7.5% OVA) and compared these effects with intratracheal instillation of OVA (1.5 mg/0.3 ml). Asthmoid responsiveness was determined by analysis of early airway responsiveness (EAR), antigen-specific IgE levels, as well as airway inflammation including the composition of T cell subpopulations in the bronchoalveolar lavage (BAL) and lung tissue with special respect to the T cell activation markers CD25 and CD26. Even low allergen doses caused allergen-specific EAR and increases of antigen-specific IgE levels. However, EAR and IgE levels did not increase dose dependently. Higher concentrations of OVA led to a dose-dependent increase of several immunological markers of allergic asthma including an influx of eosinophils, T cells, and dendritic cells. Interestingly, a dose-dependent increase of CD4 + /CD25 + /CD26 + T cells was found in the lungs. Summarizing, we established a novel F344 rat model of aerosolized OVA-induced asthma. Thereby, we found a dose-dependent recruitment of cellular markers of allergic asthma including the activated CD4 + /CD25 + /CD26 + T cell subpopulation, which has not been described in asthma yet.
Publisher: Proceedings of the National Academy of Sciences
Date: 23-01-2013
Abstract: IFN-γ is critical for immunity against infections with intracellular pathogens, such as Salmonella enterica . However, which of the many cell types capable of producing IFN-γ controls Salmonella infections remains unclear. Using a mouse model of systemic Salmonella infection, we observed that only a lack of all lymphocytes or CD90 (Thy1) + cells, but not the absence of T cells, Retinoic acid-related orphan receptor (ROR)-γt–dependent lymphocytes, (NK)1.1 + cells, natural killer T (NKT), and/or B cells alone, replicated the highly susceptible phenotype of IFN-γ–deficient mice to Salmonella infection. A combination of antibody depletions and adoptive transfer experiments revealed that early protective IFN-γ was provided by Thy1-expressing natural killer (NK) cells and that these cells improved antibacterial immunity through the provision of IFN-γ. Further analysis of NK cells producing IFN-γ in response to Salmonella indicated that less mature NK cells were more efficient at mediating antibacterial effector function than terminally differentiated NK cells. Inspired by recent reports of Thy1 + NK cells contributing to immune memory, we analyzed their role in secondary protection against otherwise lethal WT Salmonella infections. Notably, we observed that a newly generated Salmonella vaccine strain not only conferred superior protection compared with conventional regimens but that this enhanced efficiency of recall immunity was afforded by incorporating CD4 − CD8 − Thy1 + cells into the secondary response. Taken together, these findings demonstrate that Thy1-expressing NK cells play an important role in antibacterial immunity.
Publisher: Springer Science and Business Media LLC
Date: 31-12-2018
DOI: 10.1038/S41586-018-0812-9
Abstract: The immune system can suppress tumour development both by eliminating malignant cells and by preventing the outgrowth and spread of cancer cells that resist eradication
Publisher: Springer Science and Business Media LLC
Date: 15-05-2023
Publisher: American Physiological Society
Date: 07-2017
DOI: 10.1152/PHYSREV.00026.2016
Abstract: Cell surface innate immune receptors can directly detect a variety of extracellular pathogens to which cytoplasmic innate immune sensors are rarely exposed. Instead, within the cytoplasm, the environment is rife with cellular machinery and signaling pathways that are indirectly perturbed by pathogenic microbes to activate intracellular sensors, such as pyrin, NLRP1, NLRP3, or NLRC4. Therefore, subtle changes in key intracellular processes such as phosphorylation, ubiquitination, and other pathways leading to posttranslational protein modification are key determinants of innate immune recognition in the cytoplasm. This concept is critical to establish the “guard hypothesis” whereby otherwise homeostatic pathways that keep innate immune sensors at bay are released in response to alterations in their posttranslational modification status. Originally identified in plants, evidence that a similar guardlike mechanism exists in humans has recently been identified, whereby a mutation that prevents phosphorylation of the innate immune sensor pyrin triggers a dominantly inherited autoinflammatory disease. It is also noteworthy that even when a cytoplasmic innate immune sensor has a direct ligand, such as bacterial peptidoglycan (NOD1 or NOD2), RNA (RIG-I or MDA5), or DNA (cGAS or IFI16), it can still be influenced by posttranslational modification to dramatically alter its response. Therefore, due to their existence in the cytoplasmic milieu, posttranslational modification is a key determinant of intracellular innate immune receptor functionality.
Publisher: The American Association of Immunologists
Date: 06-2014
Abstract: It has been proposed that activation of dendritic cells (DCs) presenting self-antigens during inflammation may lead to activation of autoreactive T cells and the development of autoimmunity. To test this hypothesis, we examined the presentation of the autoantigen recognized in autoimmune gastritis, gastric H+/K+ ATPase, which is naturally expressed in the stomach and is constitutively presented in the stomach-draining lymph nodes. Systemic administration to mice of the TLR9 agonist CpG DNA, agonist anti-CD40 Ab, or TLR4 agonist LPS all failed to abrogate the process of peripheral clonal deletion of H+/K+ ATPase–specific CD4 T cells or promote the development of autoimmune gastritis. We demonstrated that migratory DCs from the stomach-draining lymph nodes are the only DC subset capable of constitutively presenting the endogenous gastric H+/K+ ATPase autoantigen in its normal physiological context. Analysis of costimulatory molecules indicated that, relative to resident DCs, migratory DCs displayed a partially activated phenotype in the steady state. Furthermore, migratory DCs were refractory to stimulation by transient exposure to TLR agonists, as they failed to upregulate costimulatory molecules, secrete significant amounts of inflammatory cytokines, or induce differentiation of effector T cells. Together, these data show that transient systemic inflammation failed to break tolerance to the gastric autoantigen, as migratory DCs presenting the gastric autoantigen remain tolerogenic under such conditions, demonstrating the robust nature of peripheral tolerance.
Publisher: Elsevier BV
Date: 02-2014
DOI: 10.1016/J.MIB.2013.12.004
Abstract: Salmonella enterica subsp. enterica includes several very important human serovars including Typhi, Paratyphi, Typhimurium and Enteritidis. These bacteria cause a significant global burden of disease, typically classified into enteric fever, gastroenteritis and, more recently, invasive non-typhoidal salmonellosis (iNTS). Vaccines have been developed for one of these serovars, S. Typhi and the recent increase in iNTS cases has resulted in a push to develop new vaccines that will inhibit disease by S. Typhimurium and S. Enteritidis, the most common iNTS S. enterica serovars. The development of new human vaccines has been informed by studies in the murine model of typhoid fever based on S. Typhimurium infections of very 'sensitive' (Nr -1(S)) mice, which has some obvious deficiencies, not the least that antibodies protect humans against S. Typhi infection but are only weakly protective in 'sensitive' mice infected with S. Typhimurium. S. Typhimurium also lacks Vi, the target of protective antibodies in typhoid fever. Notwithstanding these deficiencies, the murine model has identified a very complex series of innate and adaptive immune responses to infection that might be exploited to develop new vaccines. Equally, advances in understanding the pathogenesis of infection, through pathogenomics and more sophisticated animal models will likely contribute to the development of novel immunogens.
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.
Publisher: Rockefeller University Press
Date: 29-04-2021
DOI: 10.1084/JEM.20200940
Abstract: Tissue-resident memory T cells (TRM cells) are key elements of tissue immunity. Here, we investigated the role of the regulator of T cell receptor and cytokine signaling, Ptpn2, in the formation and function of TRM cells in skin. Ptpn2-deficient CD8+ T cells displayed a marked defect in generating CD69+ CD103+ TRM cells in response to herpes simplex virus type 1 (HSV-1) skin infection. This was accompanied by a reduction in the proportion of KLRG1− memory precursor cells and a transcriptional bias toward terminal differentiation. Of note, forced expression of KLRG1 was sufficient to impede TRM cell formation. Normalizing memory precursor frequencies by transferring equal numbers of KLRG1− cells restored TRM generation, demonstrating that Ptpn2 impacted skin seeding with precursors rather than downstream TRM cell differentiation. Importantly, Ptpn2-deficient TRM cells augmented skin autoimmunity but also afforded superior protection from HSV-1 infection. Our results emphasize that KLRG1 repression is required for optimal TRM cell formation in skin and reveal an important role of Ptpn2 in regulating TRM cell functionality.
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.
Publisher: Elsevier BV
Date: 12-2014
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.
Publisher: Springer Nature Switzerland
Date: 2022
Publisher: Springer Science and Business Media LLC
Date: 21-11-2018
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.
Publisher: Public Library of Science (PLoS)
Date: 17-03-2014
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.IMMUNI.2012.09.003
Abstract: In this issue of Immunity, Soudja et al. (2012) demonstrate that non-antigen-specific stimulation evoked by a variety of pathogens plays an important role in the innate acquisition of effector function by memory CD8(+) T cells.
Publisher: Elsevier BV
Date: 02-2017
Publisher: Springer Science and Business Media LLC
Date: 26-09-2016
DOI: 10.1038/NI.3565
Abstract: Mucosal-associated invariant T cells (MAIT cells) detect microbial vitamin B2 derivatives presented by the antigen-presenting molecule MR1. Here we defined three developmental stages and checkpoints for the MAIT cell lineage in humans and mice. Stage 1 and stage 2 MAIT cells predominated in thymus, while stage 3 cells progressively increased in abundance extrathymically. Transition through each checkpoint was regulated by MR1, whereas the final checkpoint that generated mature functional MAIT cells was controlled by multiple factors, including the transcription factor PLZF and microbial colonization. Furthermore, stage 3 MAIT cell populations were expanded in mice deficient in the antigen-presenting molecule CD1d, suggestive of a niche shared by MAIT cells and natural killer T cells (NKT cells). Accordingly, this study maps the developmental pathway and checkpoints that control the generation of functional MAIT cells.
Publisher: Elsevier BV
Date: 11-2002
DOI: 10.1016/S0165-5728(02)00278-3
Abstract: Sympathetic nervous system (SNS) activation mobilizes blood leukocytes. Under these circumstances, both epinephrine (EPI) and neuropeptide Y (NPY) are released. Therefore, we investigated a possible interaction between these transmitters during leukocyte mobilization, using intravenous catheterization of male adult Lewis rats. Intravenous application of NPY followed by EPI, dose-dependently facilitated, intensified and inhibited EPI-induced leukocytosis with subset-specificity for NK-cells, monocytes, and B-lymphocytes. Pharmacological assessment of NPY receptors involved revealed a Y-1R-mediated inhibition and a Y-5R-mediated facilitation. RT-PCR on peripheral blood mononuclear cells (PBMC) detected Y-1R mRNA only, suggesting direct Y-1R-mediated effects on leukocytes and indirect effects via the Y-5R. Thus, via a specific Y-1R/Y-5R interplay, NPY acts as a neuroimmune co-transmitter in vivo.
Publisher: Elsevier BV
Date: 07-2001
DOI: 10.1016/S0165-5728(01)00328-9
Abstract: Sympathetic nervous system activation mobilizes leukocytes but it is unknown whether the concomitant neuropeptide Y (NPY)-release also alters blood leukocyte counts. Using chronic intravenous (i.v.) cannulation of freely moving rats and flow cytometry, time-, dose- and subset-specific effects of NPY on blood leukocytes were investigated 1-15 min after injection: High-dose NPY increases leukocytes numbers by preferentially mobilizing CD4(+) T-cells, activated NKR-P1A(+) monocytes and NK-cells. Low-dose NPY significantly decreases B-lymphocyte and NK-cell numbers. Furthermore, NPY dose-dependently mobilizes a previously undetected IgM(low)CD5(+)CD11b(+) B-cell subpopulation in rats ("B1-like" B-lymphocytes). These data suggest a role for the sympathetic neurotransmitter NPY in neuroimmune alterations in vivo.
Publisher: Elsevier BV
Date: 08-2023
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.
Publisher: Elsevier BV
Date: 03-2008
DOI: 10.1016/J.JNEUROIM.2008.01.012
Abstract: Despite a continuously growing body of evidence highlighting the role of NPY in the immune system, surprisingly little is known about its ability to alter human leukocyte function. We therefore set out to examine NPY receptor expression and functional effects of NPY in freshly isolated human neutrophils. Our results not only demonstrate for the first time the presence of specific NPY receptors on human neutrophils, but also unveil of how these receptors differentially modulate critical functions of neutrophils such as phagocytosis of bacteria as well as the release of reactive oxygen species.
Publisher: The American Association of Immunologists
Date: 03-2010
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.
Publisher: Elsevier BV
Date: 2003
DOI: 10.1016/S0165-5728(02)00424-1
Abstract: Both cellular and humoral functions of the immune system are modulated by the sympathetic nervous system (SNS). This interaction is mainly mediated by the release of catecholamines (CA) and their receptor-specific action on immune cells. However, neuropeptide Y (NPY), also present in sympathetic nerve terminals, is released upon SNS-stimulation. NPY modulates potent immunological effects in vitro and in vivo, such as differentiation of T helper cells, monocyte mediator release, NK cell activation, and immune cell redistribution. In addition to this direct action within the neuroimmune crosstalk, NPY is also able to modulate the immunomodulatory effects of other neurotransmitters, thereby acting as a neuroimmune co-transmitter. This review will discuss key findings from recent studies, provide implications for the clinical situation, and integrate the pleiotropic functions of NPY in the context of neuroimmune interactions.
Publisher: Springer Science and Business Media LLC
Date: 2005
Publisher: Hindawi Limited
Date: 24-02-2021
DOI: 10.1111/CMI.13317
Abstract: Staphylococcus aureus is a major opportunistic human pathogen that is globally prevalent. Although S. aureus and humans may have co-evolved to the point of commensalism, the bacterium is equipped with virulence factors causing devastating infections. The adoption of an intracellular lifestyle by S. aureus is an important facet of its pathogenesis. Occupying a privileged intracellular compartment permits evasion from the bactericidal actions of host immunity and antibiotics. However, this localization exposes S. aureus to cell-intrinsic processes comprising autophagy, metabolic challenges and clearance mechanisms orchestrated by host programmed cell death pathways (PCDs), including apoptosis, pyroptosis and necroptosis. Mounting evidence suggests that S. aureus deploys pathoadaptive mechanisms that modulate the expression of its virulence factors to prevent elimination through PCD pathways. In this review, we critically analyse the current literature on the interplay between S. aureus virulence factors with the key, intertwined nodes of PCD. We discuss how S. aureus adaptation to the human host plays an essential role in the evasion of PCD, and we consider future directions to study S. aureus-PCD interactions.
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.
Publisher: The American Association of Immunologists
Date: 12-2014
Abstract: Although CD4+ T cell help (Th) is critical for inducing optimal B cell and CD8+ T cell responses, it remains unclear whether induction of CD4+ Th responses postinfection are also dependent on CD4+ T cell help. In this study, we show that activation of adoptively transferred Th cells during primary influenza A virus (IAV) infection enhances both the magnitude and functional breadth of endogenous primary IAV-specific CD4+ T cell responses. This enhancement was dependent on CD154-CD40–dependent dendritic cell licensing and resulted in a greater recall capacity of IAV-specific CD4+ and CD8+ T memory responses after heterologous IAV infection. These data suggest that engaging pre-existing CD4 responses at the time of priming may be a strategy for improving cellular immunity after vaccination.
Publisher: Public Library of Science (PLoS)
Date: 14-06-2016
Publisher: Public Library of Science (PLoS)
Date: 25-10-2021
DOI: 10.1371/JOURNAL.PPAT.1010004
Abstract: While Salmonella enterica is seen as an archetypal facultative intracellular bacterial pathogen where protection is mediated by CD4 + T cells, identifying circulating protective cells has proved very difficult, inhibiting steps to identify key antigen specificities. Exploiting a mouse model of vaccination, we show that the spleens of C57BL/6 mice vaccinated with live-attenuated Salmonella serovar Typhimurium ( S . Typhimurium) strains carried a pool of IFN-γ + CD4 + T cells that could adoptively transfer protection, but only transiently. Circulating Salmonella -reactive CD4 + T cells expressed the liver-homing chemokine receptor CXCR6, accumulated over time in the liver and assumed phenotypic characteristics associated with tissue-associated T cells. Liver memory CD4 + T cells showed TCR selection bias and their accumulation in the liver could be inhibited by blocking CXCL16. These data showed that the circulation of CD4 + T cells mediating immunity to Salmonella is limited to a brief window after which Salmonella -specific CD4 + T cells migrate to peripheral tissues. Our observations highlight the importance of triggering tissue-specific immunity against systemic infections.
Publisher: Springer Science and Business Media LLC
Date: 02-2019
DOI: 10.1038/S41586-019-0958-0
Abstract: Panel j was inadvertently labelled as panel k in the caption to Fig. 4. Similarly, 'Fig. 4k' should have been 'Fig. 4j' in the sentence beginning 'TNF-α-deficient gBT-I cells were…'. In addition, the surname of author Umaimainthan Palendira was misspelled 'Palendria'. These errors have been corrected online.
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.IMMUNI.2019.06.002
Abstract: Interactions with the microbiota influence many aspects of immunity, including immune cell development, differentiation, and function. Here, we examined the impact of the microbiota on CD8
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.
Publisher: Frontiers Media SA
Date: 21-10-2014
Publisher: Proceedings of the National Academy of Sciences
Date: 25-09-2018
Abstract: Effective vaccination against Salmonella infection requires the generation of memory T cells that can be reactivated upon exposure to bacteria in a natural setting. It is unclear whether immunity requires memory T cells that continuously patrol blood, lymphatics, and tissues, whether noncirculating T cells are important, or both. We demonstrate the generation of circulating and noncirculating memory pools after immunization. However, naive mice that previously shared a blood supply with vaccinated partners received recirculating memory T cells, but did not have T cell memory with characteristics of tissue residence, resulting in a failure to acquire robust protective immunity. Thus, noncirculating tissue-resident memory T cells are vital for effective protection against Salmonella .
Publisher: Elsevier BV
Date: 09-2020
Publisher: Wiley
Date: 04-2005
Abstract: Previous studies indicated potent inhibitory effects of beta2-adrenoceptor (beta2AR) activation on the immunological mediator release of mast cells (MC). Here, we studied effects of beta2AR agonists on human MC mediator release, and in particular on MC proliferation, adhesion, and migration. MC were isolated from human intestinal mucosa, purified, and cultured in the presence of stem cell factor (SCF). beta2AR activation by epinephrine, norepinephrine, and salbutamol suppressed the IgE receptor-dependent release of histamine, lipid mediators, and TNF-alpha, and inhibited SCF-dependent MC proliferation and migration. Moreover, beta2-adrenergic stimulation interfered with MC adhesion to fibronectin and human endothelial cells. Using fluorescent phallacidin, we found that beta2AR activation reduced the amount of filamentous actin (F-actin) within minutes, whereas MC stimulation by either IgE receptor cross-linking or SCF caused F-actin accumulation. Interestingly, this activation-induced F-actin increase was abolished by previous beta2-adrenergic stimulation. Finally, we demonstrated that disruption of the F-actin cytoskeleton by latrunculin B mimicked the effects of beta2AR agonists on MC adhesion and migration. Our results argue for an important role of F-actin interference in beta2AR-mediated MC inhibition. Furthermore, the data support the concept of neuroimmune interactions regulating intestinal MC distribution, density, and functionality in vivo.
Publisher: Oxford University Press (OUP)
Date: 14-12-2004
DOI: 10.1111/J.1365-2249.2005.02666.X
Abstract: CD26 truncates several chemokines as well as neuropeptides and influences immune responses via modulation of cell adhesion and T cell activation, suggesting an involvement of CD26 in asthmatic and airway inflammation. Therefore, Fischer 344 (F344), Brown Norway (BN) and Lewis (LEW) rat strains, which differ in their CD26-like enzymatic activity, were compared using an asthma model. Additionally, two CD26-deficient mutant F344 rat substrains were included and compared to the wild-type F344 substrain. Immunization was performed twice with ovalbumin (OVA), and 2 weeks later the rats were challenged with OVA intratracheally Flow cytometry (FACS) analysis of different leucocyte subsets as well as enzyme-linked immunosorbent assay (ELISA) for IgE levels in the blood and bronchoalveolar lavage (BAL) were performed 24 h after challenge. LEW rats with the lowest CD26 activity among the rat strains investigated here displayed significantly reduced CD4+ T cell numbers in the BAL compared to wild-type F344 and BN rats. Moreover, in asthma, the ratio of CD26+ to CD26– T cell receptor (TCR)-positive cells increased significantly in F344 and LEW but not BN rats. Most intriguingly, in both CD26-deficient F344 rat substrains the number of CD4+ T lymphocytes was markedly reduced compared to wild-type F344. The decrease in T cell recruitment observed in the CD26-deficient rats was associated with significantly reduced OVA-specific IgE-titres. This is the first report to show a remarkably reduced T cell recruitment in rat strains that either lack or exhibit reduced CD26-like enzymatic activity, suggesting a role for CD26 in the pathogenesis of asthma via T cell-dependent processes such as antibody production.
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.
Publisher: Wiley
Date: 24-08-2015
Abstract: Humans encode two inflammatory caspases that detect cytoplasmic LPS, caspase-4 and caspase-5. When activated, these trigger pyroptotic cell death and caspase-1-dependent IL-1β production however the mechanism underlying this process is not yet confirmed. We now show that a specific NLRP3 inhibitor, MCC950, prevents caspase-4/5-dependent IL-1β production elicited by transfected LPS. Given that both caspase-4 and caspase-5 can detect cytoplasmic LPS, it is possible that these proteins exhibit some degree of redundancy. Therefore, we generated human monocytic cell lines in which caspase-4 and caspase-5 were genetically deleted either in idually or together. We found that the deletion of caspase-4 suppressed cell death and IL-1β production following transfection of LPS into the cytoplasm, or in response to infection with Salmonella typhimurium. Although deletion of caspase-5 did not confer protection against transfected LPS, cell death and IL-1β production were reduced after infection with Salmonella. Furthermore, double deletion of caspase-4 and caspase-5 had a synergistic effect in the context of Salmonella infection. Our results identify the NLRP3 inflammasome as the specific platform for IL-1β maturation, downstream of cytoplasmic LPS detection by caspase-4/5. We also show that both caspase-4 and caspase-5 are functionally important for appropriate responses to intracellular Gram-negative bacteria.
Publisher: Elsevier BV
Date: 10-2004
Publisher: The American Association of Immunologists
Date: 03-2010
Abstract: Given the central role of intestinal dendritic cells (DCs) in the regulation of gut immune responses, it is not surprising that several bacterial pathogens have evolved strategies to prevent or bypass recognition by DCs. In this article, we will review recent findings on the interaction between intestinal DCs and prototypical bacterial pathogens, such as Salmonella, Yersinia, or Helicobacter. We will discuss the different approaches with which these pathogens seek to evade DC recognition and subsequent T cell activation. These erse strategies span to include mounting irrelevant immune responses, inhibition of Ag presentation by DCs, and stretch as far as to manipulate the Th1/Th2 balance of CD4+ T cells in the bacteria’s favor.
Start Date: 03-2021
End Date: 03-2024
Amount: $680,850.00
Funder: Australian Research Council
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