Tolerance of NK cells encountering their viral ligand during development

Department of Microbiology and Immunology, Cancer Research Institute, University of California San Francisco, San Francisco, CA 94143, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 08/2008; 205(8):1819-28. DOI: 10.1084/jem.20072448
Source: PubMed


During development, T and B cells encountering their cognate ligands via antigen-specific receptors are deleted or rendered anergic. Like T and B cells, natural killer (NK) cells express certain receptors, such as Ly49H, associated with immunoreceptor tyrosine-based activation motif-bearing adaptor proteins that transmit activating signals through Syk family kinases. Ly49H binds with high affinity to a mouse cytomegalovirus (MCMV)-encoded glycoprotein, m157, but does not recognize self-antigens. For comparison with the behavior of immature T and B cells exposed to foreign antigens, we addressed the fate of Ly49H(+) NK cells that encountered their viral ligand during development by retroviral transduction of bone marrow stem cells with m157. In chimeric mice expressing m157, we observed a reduction in Ly49H(+) NK cells in multiple tissues and less Ly49H on the cell surface. NK cells exposed to m157 during development appeared less mature, produced less interferon gamma when stimulated through Ly49H, and were unable to kill m157-bearing target cells. After MCMV infection, these NK cells were severely impaired in their ability to proliferate. Thus, if immature NK cells encounter ligands for their activating receptors, regulatory mechanisms exist to keep these cells in an unresponsive state.

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    • "For example, chronic exposure to NKG2D ligands in mice renders NK cells hyporesponsive to target cells (62). Similarly, when the ligand (m157) for the activating Ly49H is constitutively expressed, mouse Ly49H+ NK cells become hyporesponsive (63). Finally, NK cells in NKp46-deficient mice are more responsive, suggesting that NKp46 hampers the reactivity of NK cells via an unidentified constitutively expressed ligand (64). "
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    ABSTRACT: Expression of non-rearranged HLA class I-binding receptors characterizes human and mouse NK cells. The postulation of the missing-self hypothesis some 30 years ago triggered the subsequent search and discovery of inhibitory MHC-receptors, both in humans and mice. These receptors have two functions: (i) to control the threshold for NK cell activation, a process termed "licensing" or "education," and (ii) to inhibit NK cell activation during interactions with healthy HLA class I-expressing cells. The discovery of activating forms of KIRs (aKIR) challenged the concept of NK cell tolerance in steady state, as well as during immune challenge: what is the biological role of the activating KIR, in particular when NK cells express aKIRs in the absence of inhibitory receptors? Recently it was shown that aKIRs also participate in the education of NK cells. However, instead of lowering the threshold of activation like iKIRs, the expression of aKIRs has the opposite effect, i.e., rendering NK cells hyporesponsive. These findings may have consequences during NK cell response to viral infection, in cancer development, and in the initial stages of pregnancy. Here we review the current knowledge of activating KIRs, including the biological concept of aKIR-dependent NK cell education, and their impact in health and disease.
    Frontiers in Immunology 04/2014; 5:184. DOI:10.3389/fimmu.2014.00184
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    • "Compared with HLA-C1 donors, KIR2DS1SP NK cells from HLA-C2 homozygous individuals are hyporesponsive to a HLA-C2 positive target cell (108). Similarly, mice studies described hyporesponsiveness of activating receptor-positive NK cells resulting from in vivo chronic interaction with a viral ligand (110, 111). Recently, KIR2DS1SP NK clones displaying in vitro anti-HLA-C2 cytotoxicity have been identified in all HLA-C genotypes (112). "
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    ABSTRACT: Blurring the boundary between innate and adaptive immune system, natural killer (NK) cells are widely recognized as potent anti-leukemia mediators. Alloreactive donor NK cells have been shown to improve the outcome of allogeneic stem-cell transplantation for leukemia. In addition, in vivo transfer of NK cells may soon reveal an important therapeutic tool for leukemia, if tolerance to NK-mediated anti-leukemia effects is overcome. This will require, at a minimum, the ex vivo generation of a clinically safe NK cell product containing adequate numbers of NK cells with robust anti-leukemia potential. Ideally, ex vivo generated NK cells should also have similar anti-leukemia potential in different patients, and be easy to obtain for convenient clinical scale-up. Moreover, optimal clinical protocols for NK therapy in leukemia and other cancers are still lacking. These and other issues are being currently addressed by multiple research groups. This review will first describe current laboratory NK cell expansion and differentiation techniques by separately addressing different NK cell sources. Subsequently, it will address the mechanisms known to be responsible for NK cell alloreactivity, as well as their clinical impact in the hematopoietic stem cells transplantation setting. Finally, it will briefly provide insight on past NK-based clinical trials.
    Frontiers in Immunology 03/2014; 5:95. DOI:10.3389/fimmu.2014.00095
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    • "NK cells share an increasing number of traits with the adaptive immune system, including the formation of self-tolerance and the generation of long-lived memory cells, despite their exclusive use of germline-encoded antigen receptors (44,45). Continuous exposure of NK cells to ligands recognizing their activating receptors has been shown to result in NK cell tolerance and, therefore, argues that regulatory mechanisms exist to limit their autoimmune potential (46,47). Moreover, these experiments suggest that the expression of NKG2D ligands on activated type 1 diabetic NK cells could result in their chronic stimulation through the NKG2D receptor, inducing NK cell hyporesponsiveness. "
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    ABSTRACT: Natural killer (NK) cells from NOD mice have numeric and functional abnormalities, and restoration of NK cell function prevents autoimmune diabetes in NOD mice. However, little is known about the number and function of NK cells in humans affected by type 1 diabetes. Therefore, we evaluated the phenotype and function of NK cells in a large cohort of type 1 diabetic children. Peripheral blood mononuclear blood cells were obtained from subjects whose duration of disease was between 6 months and 2 years. NK cells were characterized by flow cytometry, enzyme-linked immunosorbent spot assays, and cytotoxicity assays. Signaling through the activating NK cell receptor, NKG2D, was assessed by immunoblotting and reverse-phase phosphoprotein lysate microarray. NK cells from type 1 diabetic subjects were present at reduced cell numbers compared with age-matched, nondiabetic control subjects and had diminished responses to the cytokines interleukin (IL)-2 and IL-15. Analysis before and after IL-2 stimulation revealed that unlike NK cells from nondiabetic control subjects, NK cells from type 1 diabetic subjects failed to downregulate the NKG2D ligands, major histocompatibility complex class I-related chains A and B, upon activation. Moreover, type 1 diabetic NK cells also exhibited decreased NKG2D-dependent cytotoxicity and interferon-γ secretion. Finally, type 1 diabetic NK cells showed clear defects in NKG2D-mediated activation of the phosphoinositide 3-kinase-AKT pathway. These results are the first to demonstrate that type 1 diabetic subjects have aberrant signaling through the NKG2D receptor and suggest that NK cell dysfunction contributes to the autoimmune pathogenesis of type 1 diabetes.
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