Abstract
The ability of natural-killer cells to regulate adaptive immunity is not well understood. Here we define an interaction between the class Ib major histocompatibility complex (MHC) molecule Qa-1-Qdm on activated T cells responsible for adaptive immunity and CD94-NKG2A inhibitory receptors expressed by natural-killer cells by using Qa-1-deficient and Qa-1 knockin mice containing a point mutation that selectively abolishes Qa-1-Qdm binding to CD94-NKG2A receptors. The Qa-1-NKG2A interaction protected activated CD4+ T cells from lysis by a subset of NKG2A+ NK cells and was essential for T cell expansion and development of immunologic memory. Antibody-dependent blockade of this Qa-1-NKG2A interaction resulted in potent NK-dependent elimination of activated autoreactive T cells and amelioration of experimental autoimmune encephalomyelitis. These findings extend the functional reach of the NK system to include regulation of adaptive T cell responses and suggest a new clinical strategy for elimination of antigen-activated T cells in the context of autoimmune disease and transplantation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Marrow / immunology
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Bone Marrow / metabolism
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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Cell Proliferation
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Cells, Cultured
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Chimerin Proteins / genetics
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Chimerin Proteins / immunology
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Chimerin Proteins / metabolism
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Encephalomyelitis, Autoimmune, Experimental / genetics
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / metabolism
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Gene Expression Regulation / immunology*
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Genetic Predisposition to Disease
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Histocompatibility Antigens Class I / genetics
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Histocompatibility Antigens Class I / metabolism*
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Immunologic Memory / immunology
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Interferon-gamma / biosynthesis
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Killer Cells, Natural / cytology
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Killer Cells, Natural / immunology*
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Killer Cells, Natural / metabolism
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Lentivirus / genetics
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Lymphocyte Activation / immunology*
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Mice
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Mice, Knockout
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NK Cell Lectin-Like Receptor Subfamily C
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NK Cell Lectin-Like Receptor Subfamily D / genetics
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NK Cell Lectin-Like Receptor Subfamily D / metabolism
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Phenotype
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Receptors, Immunologic / genetics
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Receptors, Immunologic / metabolism*
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Receptors, Natural Killer Cell
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Signal Transduction / immunology*
Substances
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Chimerin Proteins
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DNA-Binding Proteins
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Histocompatibility Antigens Class I
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Klrc1 protein, mouse
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NK Cell Lectin-Like Receptor Subfamily C
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NK Cell Lectin-Like Receptor Subfamily D
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Q surface antigens
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Rag2 protein, mouse
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Receptors, Immunologic
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Receptors, Natural Killer Cell
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Interferon-gamma