Dan Andrews

Homeostatic defects in interleukin 18‐deficient mice contribute to protection against the lethal effects of endotoxin

Publisher: Wiley

Date: 25-01-2011

DOI: 10.1038/ICB.2010.168

Abstract: Toll-like receptor-4-lipopolysaccharide (LPS)-mediated inflammation is used to delineate signals involved in cross-talk between antigen-presenting cells (APCs) and lymphocytes such as natural killer (NK) cells. Following APC stimulation and cytokine release, NK cells produce interferon (IFN)-γ. High levels of LPS induce endotoxicosis, a systemic inflammatory disease in which IFN-γ causes significant morbidity and mortality. Several studies have highlighted the role of interleukin (IL)-18, IL-1β, IL-17A and IFN-γ in the development of endotoxicosis, but whether these cytokines interact with each other is yet to be determined. Our data demonstrate that IL-18 and IL-17A have important roles in NK cell IFN-γ production during endotoxicosis. Importantly, we provide the first evidence that IL-18 also has a role in IL-17A production by T-cell receptor (TCR)-δ cells. Furthermore, we demonstrate that IL-18-deficient mice have a defect in γδ T-cell homeostasis and IL-1β production, both of which can contribute to the development of disease through induction of IL-17A. These results reveal novel requirements for IL-18 in innate immune cell homeostasis and activation, demonstrating that the role of IL-18 in innate immunity occurs at a level other than activation.

Reversion of mutations in a live mycoplasma vaccine alters its metabolism

Publisher: Elsevier BV

Date: 05-2023

DOI: 10.1016/J.VACCINE.2023.04.045

Functional interactions between dendritic cells and NK cells during viral infection

Publisher: Springer Science and Business Media LLC

Date: 23-12-2003

DOI: 10.1038/NI880

The expanding role of murine class Ib MHC in the development and activation of Natural Killer cells

Publisher: Elsevier BV

Date: 11-2018

DOI: 10.1016/J.MOLIMM.2018.05.001

Abstract: Major Histocompatibility Complex-I (MHC-I) molecules can be ided into class Ia and class Ib, with three distinct class Ib families found in the mouse. These families are designated as Q, T and M and are largely unexplored in terms of their immunological function. Among the class Ib MHC, H2-T23 (Qa-1b) has been a significant target for Natural Killer (NK) cell research, owing to its homology with the human class Ib human leukocyte antigen (HLA)-E. However, recent data has indicated that members of the Q and M family of class Ib MHC also play a critical role in the development and regulation NK cells. Here we discuss the recent advances in the control of NK cells by murine class Ib MHC as a means to stimulate further exploration of these molecules.

A role for granzyme M in TLR4-driven inflammation and endotoxicosis

Publisher: The American Association of Immunologists

Date: 08-2010

DOI: 10.4049/JIMMUNOL.1000430

Abstract: Lymphocyte perforin and serine protease granzymes are well-recognized extrinsic mediators of apoptosis. We now demonstrate that cytotoxic lymphocyte granule components profoundly augment the myeloid cell inflammatory cytokine cascade in response to TLR4 ligation. Whereas caspase-1–deficient mice were completely resistant to LPS, reduced serum cytokine production and resistance to lethal endotoxicosis were also obtained with perforin-deficient mice, indicating a role for granzymes. Consistently, a lack of granzyme M (GrzM) resulted in reduced serum IL-1α, IL-1β, TNF, and IFN-γ levels and significantly reduced susceptibility to lethal endotoxicosis. These altered responses were also observed in granzyme A-deficient but not granzyme B-deficient mice. A role for APC–NK cell cross-talk in the inflammatory cascade was highlighted, as GrzM was exclusively expressed by NK cells and resistance to LPS was also observed on a RAG-1/GrzM-double deficient background. Collectively, the data suggest that NK cell GrzM augments the inflammatory cascade downstream of LPS-TLR4 signaling, which ultimately results in lethal endotoxicosis. Most importantly, these data demonstrate that granzymes should no longer be considered solely as mediators of apoptosis, but additionally as potential key regulators of inflammation.

The interaction of KIR3DL1*001 with HLA class I molecules is dependent upon molecular microarchitecture within the Bw4 epitope

Publisher: The American Association of Immunologists

Date: 15-01-2015

DOI: 10.4049/JIMMUNOL.1402542

Abstract: The killer cell Ig-like receptor 3DL1 (KIR3DL1) inhibits activation of NK cells upon interaction with HLA class I molecules such as HLA-B*57:01, which contains the Bw4 epitope spanning residues 77–83 (e.g., NLRIALR), and not with HLA allomorphs that possess the Bw6 motif (e.g., HLA-B*08:01), which differ at residues 77, 80, 81, 82, and 83. Although Bw4 residues Ile80 and Arg83 directly interact with KIR3DL1*001, their precise role in determining KIR3DL1-HLA-Bw4 specificity remains unclear. Recognition of HLA-B*57:01 by either KIR3DL1+ NK cells or the NK cell line YTS transfected with KIR3DL1*001 was impaired by mutation of residues 80 and 83 of HLA-B*57:01 to the corresponding amino acids within the Bw6 motif. Conversely, the simultaneous introduction of three Bw4 residues at positions 80, 82, and 83 into HLA-B*08:01 conferred an interaction with KIR3DL1*001. Structural analysis of HLA-B*57:01, HLA-B*08:01, and mutants of each bearing substitutions at positions 80 and 83 revealed that Ile80 and Arg83 within the Bw4 motif constrain the conformation of Glu76, primarily through a salt bridge between Arg83 and Glu76. This salt bridge was absent in HLA-Bw6 molecules as well as position 83 mutants of HLA-B*57:01. Mutation of the Bw4 residue Ile80 also disrupted this salt bridge, providing further insight into the role that position 80 plays in mediating KIR3DL1 recognition. Thus, the strict conformation of HLA-Bw4 allotypes, held in place by the Glu76–Arg83 interaction, facilitates KIR3DL1 binding, whereas Bw6 allotypes present a platform on the α1 helix that is less permissive for KIR3DL1 binding.

A novel checkpoint in the Bcl-2–regulated apoptotic pathway revealed by murine cytomegalovirus infection of dendritic cells

Publisher: Rockefeller University Press

Date: 07-09-2004

DOI: 10.1083/JCB.200403010

Abstract: Infection with murine cytomegalovirus (MCMV) has contributed to understanding many aspects of human infection and, additionally, has provided important insight to understanding complex cellular responses. Dendritic cells (DCs) are a major target for MCMV infection. Here, we analyze the effects of MCMV infection on DC viability, and show that infected DCs become resistant to apoptosis induced by growth factor deprivation. The precise contribution of changes in the expression of Bcl-2 family proteins has been assessed and a new checkpoint in the apoptotic pathway identified. Despite their resistance to apoptosis, MCMV-infected DCs showed Bax to be tightly associated with mitochondria and, together with Bak, forming high molecular weight oligomers, changes normally associated with apoptotic cell death. Exposure of a constitutively occluded Bax NH2-terminal epitope was blocked after infection. These results suggest that MCMV has evolved a novel strategy for inhibiting apoptosis and provide evidence that apoptosis can be regulated after translocation, integration, and oligomerization of Bax at the mitochondrial membrane.

Stress gets under your skin

Publisher: Springer Science and Business Media LLC

Date: 02-2008

DOI: 10.1038/NI0208-119

Ribosylation of the CD8αβ heterodimer permits binding of the nonclassical major histocompatibility molecule, H2-Q10

Publisher: Elsevier BV

Date: 10-2021

DOI: 10.1016/J.JBC.2021.101141

The murine CD94/NKG2 ligand, Qa-1b, is a high-affinity, functional ligand for the CD8αα homodimer

Publisher: Elsevier BV

Date: 03-2020

DOI: 10.1074/JBC.RA119.010509

The SMAC mimetic, LCL-161, reduces survival in aggressive MYC-driven lymphoma while promoting susceptibility to endotoxic shock

Publisher: Springer Science and Business Media LLC

Date: 04-04-2016

DOI: 10.1038/ONCSIS.2016.26

Abstract: Inhibitor of apoptosis proteins (IAPs) antagonize caspase activation and regulate death receptor signaling cascades. LCL-161 is a small molecule second mitochondrial activator of caspase (SMAC) mimetic, which both disengages IAPs from caspases and induces proteasomal degradation of cIAP-1 and -2, resulting in altered signaling through the NFκB pathway, enhanced TNF production and sensitization to apoptosis mediated by the extrinsic pathway. SMAC mimetics are undergoing clinical evaluation in a range of hematological malignancies. Burkitt-like lymphomas are hallmarked by a low apoptotic threshold, conveying sensitivity to a range of apoptosis-inducing stimuli. While evaluating LCL-161 in the Eμ- Myc model of aggressive Burkitt-like lymphoma, we noted unexpected resistance to apoptosis induction despite ‘on-target’ IAP degradation and NFκB activation. Moreover, LCL-161 treatment of lymphoma-bearing mice resulted in apparent disease acceleration concurrent to augmented inflammatory cytokine-release in the same animals. Indiscriminate exposure of lymphoma patients to SMAC mimetics may therefore be detrimental due to both unanticipated prolymphoma effects and increased susceptibility to endotoxic shock.

Recognition of the major histocompatibility complex (MHC) class Ib molecule H2-Q10 by the natural killer cell receptor Ly49C

Publisher: Elsevier BV

Date: 09-2016

DOI: 10.1074/JBC.M116.737130

The receptors CD96 and CD226 oppose each other in the regulation of natural killer cell functions

Publisher: Springer Science and Business Media LLC

Date: 23-03-2014

DOI: 10.1038/NI.2850

Abstract: CD96, CD226 (DNAM-1) and TIGIT belong to an emerging family of receptors that interact with nectin and nectin-like proteins. CD226 activates natural killer (NK) cell-mediated cytotoxicity, whereas TIGIT reportedly counterbalances CD226. In contrast, the role of CD96, which shares the ligand CD155 with CD226 and TIGIT, has remained unclear. In this study we found that CD96 competed with CD226 for CD155 binding and limited NK cell function by direct inhibition. As a result, Cd96(-/-) mice displayed hyperinflammatory responses to the bacterial product lipopolysaccharide (LPS) and resistance to carcinogenesis and experimental lung metastases. Our data provide the first description, to our knowledge, of the ability of CD96 to negatively control cytokine responses by NK cells. Blocking CD96 may have applications in pathologies in which NK cells are important.

Type I NKT-cell-mediated TNF-α is a positive regulator of NLRP3 inflammasome priming

Publisher: Wiley

Date: 29-04-2014

DOI: 10.1002/EJI.201344329

Abstract: The NLRP3 inflammasome plays a crucial role in the innate immune response to pathogens and exogenous or endogenous danger signals. Its activity must be precisely and tightly regulated to generate tailored immune responses. However, the immune cell subsets and cytokines controlling NLRP3 inflammasome activity are still poorly understood. Here, we have shown a link between NKT-cell-mediated TNF-α and NLRP3 inflammasome activity. The NLRP3 inflammasome in APCs was critical to potentiate NKT-cell-mediated immune responses, since C57BL/6 NLRP3 inflammasome-deficient mice exhibited reduced responsiveness to α-galactosylceramide. Importantly, NKT cells were found to act as regulators of NLRP3 inflammasome signaling, as NKT-cell-derived TNF-α was required for optimal IL-1β and IL-18 production by myeloid cells in response to α-galactosylceramide, by acting on the NLRP3 inflammasome priming step. Thus, NKT cells play a role in the positive regulation of NLRP3 inflammasome priming by mediating the production of TNF-α, thus demonstrating another means by which NKT cells control early inflammation.

Structural basis for the recognition of nectin-like protein-5 by the human-activating immune receptor, DNAM-1

Publisher: Elsevier BV

Date: 08-2019

DOI: 10.1074/JBC.RA119.009261

Serglycin determines secretory granule repertoire and regulates natural killer cell and cytotoxic T lymphocyte cytotoxicity

Publisher: Wiley

Date: 22-01-2016

DOI: 10.1111/FEBS.13649

Abstract: The anionic proteoglycan serglycin is a major constituent of secretory granules in cytotoxic T lymphocyte (CTL)/natural killer (NK) cells, and is proposed to promote the safe storage of the mostly cationic granule toxins, granzymes and perforin. Despite the extensive defects of mast cell function reported in serglycin gene-disrupted mice, no comprehensive study of physiologically relevant CTL/NK cell populations has been reported. We show that the cytotoxicity of serglycin-deficient CTL and NK cells is severely compromised but can be partly compensated in both cell types when they become activated. Reduced intracellular granzyme B levels were noted, particularly in CD27(+) CD11b(+) mature NK cells, whereas serglycin(-/-) TCR-transgenic (OTI) CD8 T cells also had reduced perforin stores. Culture supernatants from serglycin(-/-) OTI T cells and interleukin-2-activated NK contained increased granzyme B, linking reduced storage with heightened export. By contrast, granzyme A was not significantly reduced in cells lacking serglycin, indicating differentially regulated trafficking and/or storage for the two granzymes. A quantitative analysis of different granule classes by transmission electronmicroscopy showed a selective loss of dense-core granules in serglycin(-/-) CD8(+) CTLs, although other granule types were maintained quantitatively. The findings of the present study show that serglycin plays a critical role in the maturation of dense-core cytotoxic granules in cytotoxic lymphocytes and the trafficking and storage of perforin and granzyme B, whereas granzyme A is unaffected. The skewed retention of cytotoxic effector molecules markedly reduces CTL/NK cell cytotoxicity, although this is partly compensated for as a result of activating the cells by physiological means.

The early kinetics of cytomegalovirus-specific CD8⁺ T-cell responses are not affected by antigen load or the absence of perforin or gamma interferon

Publisher: American Society for Microbiology

Date: 15-05-2008

DOI: 10.1128/JVI.02127-07

Abstract: Both innate and adaptive immune responses participate in the control of murine cytomegalovirus (mCMV) infection. In some mouse strains, like BALB/c, the control of infection relies on the activities of CD8 + T cells. mCMV-specific CD8 + T-cell responses are unusual in that, even after mCMV has been controlled in the periphery, the numbers of circulating virus-specific CD8 + T cells remain high compared to those observed in other viral infections. To better understand the generation and maintenance of mCMV-specific CD8 + T-cell responses, we evaluated how antigen load and effector molecules, such as perforin (Prf) and gamma interferon (IFN-γ), influence these responses during acute infection in vivo. Viral burden affected the magnitude, but not the early kinetics, of antigen-specific CD8 + T-cell responses. Similarly, the magnitude of virus-specific CD8 + T-cell expansion was affected by Prf and IFN-γ, but contraction of antigen-specific responses occurred normally in both Prf- and IFN-γ-deficient mice. These data indicate that control of mCMV-specific CD8 + T-cell expansion and contraction is more complex than anticipated and, despite the role of Prf or IFN-γ in controlling viral replication, a full program of T-cell expansion and contraction can occur in their absence.

Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer

Publisher: American Association for Cancer Research (AACR)

Date: 11-2015

DOI: 10.1158/2326-6066.CIR-15-0065

Abstract: Metastatic progression is the major cause of breast cancer–related mortality. By examining multiple syngeneic preclinical breast cancer models in mice lacking a functional type-I interferon receptor (Ifnar1−/− mice), we show that host-derived type-I interferon (IFN) signaling is a critical determinant of metastatic spread that is independent of primary tumor growth. In particular, we show that bone metastasis can be accelerated in Balb/c Ifnar1−/− mice bearing either 4T1 or 66cl4 orthotopic tumors and, for the first time, present data showing the development of bone metastasis in the C57Bl/6 spontaneous MMTV-PyMT–driven model of tumorigenesis. Further exploration of these results revealed that endogenous type-I IFN signaling to the host hematopoietic system is a key determinant of metastasis-free survival and critical to the responsiveness of the circulating natural killer (NK)–cell population. We find that in vivo–stimulated NK cells derived from wild-type, but not Ifnar1−/−, mice can eliminate the 4T1 and 66cl4 breast tumor lines with varying kinetics in vitro. Together, this study indicates that the dysregulated immunity resulting from a loss of host type-I IFN signaling is sufficient to drive metastasis, and provides a rationale for targeting the endogenous type-I IFN pathway as an antimetastatic strategy. Cancer Immunol Res 3(11) 1207–17. ©2015 AACR.

DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors

Publisher: Rockefeller University Press

Date: 24-11-2008

DOI: 10.1084/JEM.20081752

Abstract: Natural killer (NK) cells and CD8 T cells require adhesion molecules for migration, activation, expansion, differentiation, and effector functions. DNAX accessory molecule 1 (DNAM-1), an adhesion molecule belonging to the immunoglobulin superfamily, promotes many of these functions in vitro. However, because NK cells and CD8 T cells express multiple adhesion molecules, it is unclear whether DNAM-1 has a unique function or is effectively redundant in vivo. To address this question, we generated mice lacking DNAM-1 and evaluated DNAM-1–deficient CD8 T cell and NK cell function in vitro and in vivo. Our results demonstrate that CD8 T cells require DNAM-1 for co-stimulation when recognizing antigen presented by nonprofessional antigen-presenting cells in contrast, DNAM-1 is dispensable when dendritic cells present the antigen. Similarly, NK cells require DNAM-1 for the elimination of tumor cells that are comparatively resistant to NK cell–mediated cytotoxicity caused by the paucity of other NK cell–activating ligands. We conclude that DNAM-1 serves to extend the range of target cells that can activate CD8 T cell and NK cells and, hence, may be essential for immunosurveillance against tumors and/or viruses that evade recognition by other activating or accessory molecules.

Receptors that interact with nectin and nectin-like proteins in the immunosurveillance and immunotherapy of cancer

Publisher: Elsevier BV

Date: 04-2012

DOI: 10.1016/J.COI.2012.01.009

Abstract: Management of an immune response is achieved through a delicate balance of pro-inflammatory and anti-inflammatory mechanisms. Controlling this response requires co-operation between a multitude of immune cells that are in turn controlled by specific receptor-ligand interactions and cytokine networks. In the context of cancer, a major mechanism by which the immune system restrains disease is through the action of cytotoxic lymphocytes that include natural killer (NK) cells and CD8 T cells. Both of these cell types express a panoply of receptors that are able to control their responses in order to heighten the specificity of their effector function. An emerging class of such receptors on cytotoxic lymphocytes are a group of immunoglobulin superfamily members that interact with ligands of the nectin and nectin-like (necl) family. These receptors include CD226, TIGIT, CRTAM and CD96. This review will outline the immunobiology of these receptors, the contexts where their function is important, their role in tumour immunosurveillance, and how they may be utilised for therapeutic applications in cancer.

Natural killer cells in viral infection: more than just killers

Publisher: Wiley

Date: 07-11-2006

DOI: 10.1111/J.1600-065X.2006.00465.X

Cancer immunoediting by the innate immune system in the absence of adaptive immunity

Publisher: Rockefeller University Press

Date: 27-08-2012

DOI: 10.1084/JEM.20112738

Abstract: Cancer immunoediting is the process whereby immune cells protect against cancer formation by sculpting the immunogenicity of developing tumors. Although the full process depends on innate and adaptive immunity, it remains unclear whether innate immunity alone is capable of immunoediting. To determine whether the innate immune system can edit tumor cells in the absence of adaptive immunity, we compared the incidence and immunogenicity of 3′methylcholanthrene-induced sarcomas in syngeneic wild-type, RAG2−/−, and RAG2−/−x γc−/− mice. We found that innate immune cells could manifest cancer immunoediting activity in the absence of adaptive immunity. This activity required natural killer (NK) cells and interferon γ (IFN-γ), which mediated the induction of M1 macrophages. M1 macrophages could be elicited by administration of CD40 agonists, thereby restoring editing activity in RAG2−/−x γc−/− mice. Our results suggest that in the absence of adaptive immunity, NK cell production of IFN-γ induces M1 macrophages, which act as important effectors during cancer immunoediting.

Cancer vaccines for established cancer: How to make them better?

Publisher: Wiley

Date: 19-03-2008

DOI: 10.1111/J.1600-065X.2008.00612.X

Interaction between conventional dendritic cells and natural killer cells is integral to the activation of effective antiviral immunity

Publisher: Springer Science and Business Media LLC

Date: 04-09-2005

DOI: 10.1038/NI1244

Abstract: Dendritic cells (DCs) regulate various aspects of innate immunity, including natural killer (NK) cell function. Here we define the mechanisms involved in DC-NK cell interactions during viral infection. NK cells were efficiently activated by murine cytomegalovirus (MCMV)-infected CD11b(+) DCs. NK cell cytotoxicity required interferon-alpha and interactions between the NKG2D activating receptor and NKG2D ligand, whereas the production of interferon-gamma by NK cells relied mainly on DC-derived interleukin 18. Although Toll-like receptor 9 contributes to antiviral immunity, we found that signaling pathways independent of Toll-like receptor 9 were important in generating immune responses to MCMV, including the production of interferon-alpha and the induction of NK cell cytotoxicity. Notably, adoptive transfer of MCMV-activated CD11b(+) DCs resulted in improved control of MCMV infection, indicating that these cells participate in controlling viral replication in vivo.

Measures of tracheal lesions are more discriminatory and reproducible indications of chronic respiratory disease caused by Mycoplasma gallisepticum in poultry

Publisher: Informa UK Limited

Date: 08-2022

DOI: 10.1080/03079457.2022.2103396

Non-classical MHC class I molecules regulating natural killer cell function

Publisher: Informa UK Limited

Date: 03-2013

DOI: 10.4161/ONCI.23336

Unconventional T Cell Targets for Cancer Immunotherapy

Publisher: Elsevier BV

Date: 03-2018

DOI: 10.1016/J.IMMUNI.2018.03.009

Abstract: Most studies on the immunotherapeutic potential of T cells have focused on CD8 and CD4 T cells that recognize peptide antigens (Ag) presented by polymorphic major histocompatibility complex (MHC) class I and MHC class II molecules, respectively. However, unconventional T cells, which interact with MHC class Ib and MHC-I like molecules, are also implicated in tumor immunity, although their role therein is unclear. These include unconventional T cells targeting MHC class Ib molecules such as HLA-E and its murine ortholog Qa-1b, natural killer T (NKT) cells, mucosal associated invariant T (MAIT) cells, and γδ T cells. Here, we review the current understanding of the roles of these unconventional T cells in tumor immunity and discuss why further studies into the immunotherapeutic potential of these cells is warranted.

NK cell intrinsic regulation of MIP-1α by granzyme M

Publisher: Springer Science and Business Media LLC

Date: 13-03-2014

DOI: 10.1038/CDDIS.2014.74

Mice deficient in heparanase exhibit impaired dendritic cell migration and reduced airway inflammation.

Publisher: Wiley

Date: 14-02-2014

DOI: 10.1002/EJI.201343645

Abstract: Heparanase is a β-d-endoglucuronidase that cleaves heparan sulphate, a key component of the ECM and basement membrane. The remodelling of the ECM by heparanase has been proposed to regulate both normal physiological and pathological processes, including wound healing, inflammation, tumour angiogenesis and cell migration. Heparanase is also known to exhibit non-enzymatic functions by regulating cell adhesion, cell signalling and differentiation. In this study, constitutive heparanase-deficient (Hpse(-/-) ) mice were generated on a C57BL/6 background using the Cre/loxP recombination system, with a complete lack of heparanase mRNA, protein and activity. Although heparanase has been implicated in embryogenesis and development, Hpse(-/-) mice are anatomically normal and fertile. Interestingly, consistent with the suggested function of heparanase in cell migration, the trafficking of dendritic cells from the skin to the draining lymph nodes was markedly reduced in Hpse(-/-) mice. Furthermore, the ability of Hpse(-/-) mice to generate an allergic inflammatory response in the airways, a process that requires dendritic cell migration, was also impaired. These findings establish an important role for heparanase in immunity and identify the enzyme as a potential target for regulation of an immune response.

Functional dissection of the granzyme family: Cell death and inflammation

Publisher: Wiley

Date: 28-04-2010

DOI: 10.1111/J.0105-2896.2010.00907.X

Abstract: Cytotoxic lymphocytes rapidly respond and destroy both malignant cells and cells infected with intracellular pathogens. One mechanism, known as granule exocytosis, employs the secretory granules of these lymphocytes. These include the pore-forming protein perforin (pfp) and a family of serine proteases known as granzymes that cleave and activate effector molecules within the target cell. Over the past two decades, the study of granzymes has largely focused on the ability of these serine proteases to induce cell death. More recently, sophisticated mouse models of disease coupled with gene-targeted mice have allowed investigators to ask why granzyme subfamilies are encoded on different chromosomal loci and what broader role these enzymes might play in inflammation and immune response. Here, we provide a brief overview of the granzyme superfamily, their relationship to pfp, and their reported functions in apoptosis. This overview is followed by a comprehensive analysis of the less characterized and developing field regarding the non-apoptotic functions of granzymes.

A potential role for RAG-1 in NK cell development revealed by analysis of NK cells during ontogeny

Publisher: Wiley

Date: 12-2010

DOI: 10.1038/ICB.2009.94

Abstract: Little is known regarding natural killer (NK) cell development in hematopoietic and visceral organs during ontogeny. We sought to determine NK cell accumulation during ontogeny and whether organ-specific niches altered development. Neonatal NK cells in the bone marrow, spleen and lung exist as immature CD27(+)/CD11B(lo) cells. The first appearance of mature CD27(lo)/CD11B(+) cells occurs at 3 weeks of age whereas maturation is complete by 8 weeks. In contrast, maturation of liver NK cells is essentially finished at 2 weeks. A role for RAG-1 (recombination-activating gene-1 product) in NK cell development was suggested as RAG-1-deficient mice accumulated NK cells differently. Surprisingly, bone marrow and spleen NK cells are absent in neonatal RAG-1(-/-) mice and an overrepresentation of a precursor NK cell subset, found normally in the liver, was observed in the bone marrow of RAG-1(-/-) mice. As mice lacking specific adaptive immune elements, including T and/or B cells, have normal NK cell repertoires, a more direct role for RAG during NK cell development cannot be excluded. Liver NK cells may represent an independent pool of cells from those developing out of the bone marrow, and RAG-1 itself may have a significant role in NK cell development.

Recognition of the nonclassical MHC class I molecule H2-M3 by the receptor Ly49A regulates the licensing and activation of NK cells

Publisher: Springer Science and Business Media LLC

Date: 11-11-2012

DOI: 10.1038/NI.2468

Subset Analysis of Human and Mouse Mature NK Cells

Publisher: Humana Press

Date: 09-11-2009

DOI: 10.1007/978-1-60761-362-6_3

Abstract: Identification of natural killer (NK) cell subsets has gained attention with the recent discovery that mature mouse NK cells comprise two distinct stages. Delineation of the stages is performed using the markers CD27 and CD11b on gated NK cells. The significance of this finding is underpinned by recent discoveries that mature human NK cells can also be discriminated by differential expression of CD27. This chapter will describe the methods required for the purification of lymphocytes from blood and other organs and the delineation of NK cell subsets by flow cytometry.

Challenges in Vaccinating Layer Hens against Salmonella Typhimurium

Publisher: MDPI AG

Date: 19-11-2020

DOI: 10.3390/VACCINES8040696

Abstract: Salmonella Typhimurium is among the most common causes of bacterial foodborne gastrointestinal disease in humans. Food items containing raw or undercooked eggs are frequently identified during traceback investigation as the source of the bacteria. Layer hens can become persistently infected with Salmonella Typhimurium and intermittently shed the bacteria over the course of their productive lifetime. Eggs laid in a contaminated environment are at risk of potential exposure to bacteria. Thus, mitigating the bacterial load on farms aids in the protection of the food supply chain. Layer hen producers use a multifaceted approach for reducing Salmonella on farms, including the all-in-all-out management strategy, strict biosecurity, sanitization, and vaccination. The use of live attenuated Salmonella vaccines is favored because they elicit a broader host immune response than killed or inactivated vaccines that have been demonstrated to provide cross-protection against multiple serovars. Depending on the vaccine, two to three doses of Salmonella Typhimurium vaccines are generally administered to layer hens within the first few weeks. The productive life of a layer hen, however, can exceed 70 weeks and it is unclear whether current vaccination regimens are effective for that extended period. The objective of this review is to highlight layer hen specific challenges that may affect vaccine efficacy.

Application of CD27 as a marker for distinguishing human NK cell subsets

Publisher: Oxford University Press (OUP)

Date: 07-03-2008

DOI: 10.1093/INTIMM/DXN022

Abstract: It has long been recognized that human NK cells can be ided into two phenotypically and functionally distinct subsets, based on their levels of expression of CD56. We recently found that CD27 distinguishes subsets of mature mouse NK cells. Here we report that CD27 can be used as a marker to discriminate human NK cell subsets. The majority of peripheral blood human NK cells were CD27(lo)/CD56(dim) NK cells, whereas the minor CD27(hi) NK cell population correspondingly displayed a CD56(bright) phenotype. Distinctions between CD27(lo) and CD27(hi) NK cells in their receptor expression and typical NK cell functions such as cytotoxicity and cytokine production can be easily delineated. Therefore, we propose the dual use of CD27 and CD56 as maturation/subset markers for human NK cells. The identification of CD27 subsets in both mice and humans will allow more accurate projections of the role of NK cell subsets in murine models of human pathologies where NK cells are involved.

Infection of dendritic cells by murine cytomegalovirus induces functional paralysis

Publisher: Springer Science and Business Media LLC

Date: 22-10-2001

DOI: 10.1038/NI724

DNAM-1/CD155 Interactions Promote Cytokine and NK Cell-Mediated Suppression of Poorly Immunogenic Melanoma Metastases

Publisher: The American Association of Immunologists

Date: 27-12-2009

DOI: 10.4049/JIMMUNOL.0903225

Abstract: A role for NK cells in therapeutic intervention for hematologic malignancies, such as acute myeloid leukemia and multiple myeloma, and nonhematologic malignancies, such as melanoma, is becoming more apparent. DNAM-1 is an NK cell receptor whose importance in facilitating activation signals received by NK cells in natural and cytokine-driven responses to tumor metastases in vivo is poorly explored. In this study, we used matched tumor lines expressing a variety of relevant ligands, neutralizing monoclonal Abs, and DNAM-1 gene-targeted mice to determine the relative importance of DNAM-1–ligand interactions in controlling tumor metastases. Our results demonstrate that NK cells require DNAM-1 for natural or cytokine (IL-2, IL-12, or IL-21) suppression of tumor metastases or their variants expressing CD70 or CD80. In contrast, DNAM-1 was dispensable when tumor cells were targets of Ab-dependent cellular cytotoxicity or presented ligands for NKG2D. CD155 appeared to be a key ligand recognized by DNAM-1 in NK cell-mediated suppression of metastases, and DNAM-1-mediated suppression coincided with perforin activity. Overall, these data implied a general role for DNAM-1-CD155 interactions in NK cell-mediated killing of tumors, even in the presence of tumor CD70 or CD80 expression, and further defined the optimal efficacy requirements of cytokines that directly activate NK cells.

Gender differences in expression of the human caspase-12 long variant determines susceptibility to Listeria monocytogenes infection

Publisher: Proceedings of the National Academy of Sciences

Date: 02-06-2009

DOI: 10.1073/PNAS.0813362106

Abstract: Inflammatory caspases are important effectors of innate immunity. Caspase-12 , of the inflammatory caspase subfamily, is expressed in all mammals tested to date, but has acquired deleterious mutation in humans. A single-nucleotide polymorphism introduces a premature stop codon in caspase-12 in the majority of the population. However, in 20% of African descendants, caspase-12 is expressed and sensitizes to infections and sepsis. Here, we examined the modalities by which human caspase-12 confers susceptibility to infection. We have generated a fully humanized mouse that expresses the human caspase-12 rare variant (Csp-12L) in a mouse casp-12 −/− background. Characterization of the humanized mouse uncovered sex differences in Csp-12L expression and gender disparity in innate immunity to Listeria monocytogenes infection. The Csp-12L transgene completely reversed the knockout resistance-to-infection phenotype in casp-12 −/− males. In contrast, it had a marginal effect on the response of female mice. We found that estrogen levels modulated the expression of caspase-12. Csp-12L was expressed in male mice but its expression was repressed in female mice. Administration of 17-β-estradiol (E2) to humanized male mice had a direct suppressive effect on Csp-12L expression and conferred relative resistance to infection. Chromatin immunoprecipitation experiments revealed that caspase-12 is a direct transcriptional target of the estrogen receptor alpha (ERα) and mapped the estrogen response element (ERE) to intron 7 of the gene. We propose that estrogen-mediated inhibition of Csp-12L expression is a built-in mechanism that has evolved to protect females from infection.

Can NK cells be a therapeutic target in human cancer?

Publisher: Wiley

Date: 11-2008

DOI: 10.1002/EJI.200838764

Abstract: Our current knowledge of NK-cell recognition and effector function suggests that it will be possible to design various new NK-cell-based immunotherapies against human cancer. The application of NK cells is already showing promise using HLA-mismatched haematopoietic stem cell transplantation for treatment of haematological malignancies. A better understanding of NK-cell heterogeneity and function will only broaden the applications for human cancer. Here we review the key developments that will propel this field.

Primary Tumor Hypoxia Recruits CD11b+/Ly6Cmed/Ly6G+ Immune Suppressor Cells and Compromises NK Cell Cytotoxicity in the Premetastatic Niche

Publisher: American Association for Cancer Research (AACR)

Date: 14-08-2012

DOI: 10.1158/0008-5472.CAN-11-3873

Abstract: Hypoxia within a tumor acts as a strong selective pressure that promotes angiogenesis, invasion, and metastatic spread. In this study, we used immune competent bone marrow chimeric mice and syngeneic orthotopic mammary cancer models to show that hypoxia in the primary tumor promotes premetastatic niche formation in secondary organs. Injection of mice with cell-free conditioned medium derived from hypoxic mammary tumor cells resulted in increased bone marrow–derived cell infiltration into the lung in the absence of a primary tumor and led to increased metastatic burden in mammary and melanoma experimental metastasis models. By characterizing the composition of infiltrating bone marrow–derived cells, we identified CD11b+/Ly6Cmed/Ly6G+ myeloid and CD3−/NK1.1+ immune cell lineages as key constituents of the premetastatic niche. Furthermore, the cytotoxicity of natural killer (NK) cells was significantly decreased, resulting in a reduced antitumor response that allowed metastasis formation in secondary organs to a similar extent as ablation of NK cells. In contrast, metastatic burden was decreased when active NK cells were present in premetastatic lungs. Together, our findings suggest that primary tumor hypoxia provides cytokines and growth factors capable of creating a premetastatic niche through recruitment of CD11b+/Ly6Cmed/Ly6G+ myeloid cells and a reduction in the cytotoxic effector functions of NK cell populations. Cancer Res 72(16) 3906–11. ©2012 AACR.

Contribution of Thy1+ NK cells to protective IFN-γ production during Salmonella Typhimurium infections

Publisher: Proceedings of the National Academy of Sciences

Date: 23-01-2013

DOI: 10.1073/PNAS.1222047110

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.

Multiple receptors converge on H2-Q10 to regulate NK and γδT-cell development

Publisher: Wiley

Date: 13-01-2019

DOI: 10.1111/IMCB.12222

Abstract: Class Ib major histocompatibility complex (MHC) is an extended family of molecules, which demonstrate tissue-specific expression and presentation of monomorphic antigens. These characteristics tend to imbue class Ib MHC with unique functions. H2-Q10 is potentially one such molecule that is overexpressed in the liver but its immunological function is not known. We have previously shown that H2-Q10 is a ligand for the natural killer cell receptor Ly49C and now, using H2-Q10-deficient mice, we demonstrate that H2-Q10 can also stabilize the expression of Qa-1b. In the absence of H2-Q10, the development and maturation of conventional hepatic natural killer cells is disrupted. We also provide evidence that H2-Q10 is a new high affinity ligand for CD8αα and controls the development of liver-resident CD8αα γδT cells. These data demonstrate that H2-Q10 has multiple roles in the development of immune subsets and identify an overlap of recognition within the class Ib MHC that is likely to be relevant to the regulation of immunity.

Lions Eye Institute

Location: Australia

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Bioproperties Pty Ltd

Location: Australia

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Monash University

Location: Australia

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University Of Western Australia

Location: Australia

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Peter MacCallum Cancer Institute

Location: Australia

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The Unique Nature Of Gamma Delta T Cell Recognition Resolved Through Interaction With H2-Q10

Start Date: 2018

End Date: 2020

Funder: National Health and Medical Research Council

Salmonella In Poultry: Improving Vaccine Efficacy

Start Date: 2020

End Date: 2023

Funder: Australian Research Council

A “Goldilocks” Live Attenuated Poultry Vaccine For Infectious Coryza

Start Date: 2022

End Date: 2026

Funder: Australian Research Council

Reducing The Health & Economic Burden Of Campylobacter Using A Live Vaccine

Start Date: 2021

End Date: 2025

Funder: Australian Research Council

Linkage Projects - Grant ID: LP210301365

Start Date: 07-2023

End Date: 07-2027

Amount: $626,114.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP190100864

Start Date: 11-2020

End Date: 11-2023

Amount: $390,000.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP190100114

Start Date: 06-2021

End Date: 06-2025

Amount: $989,000.00

Funder: Australian Research Council