Abstract
Tumor-associated ligands of the activating NKG2D receptor can effectively stimulate T cell responses at early but not late stages of tumor growth. In late-stage human tumor settings, we observed MIC-driven proliferation of NKG2D(+)CD4(+) T cells that produced the cytokine Fas ligand (FasL) as a result of NKG2D costimulation but were themselves protected from Fas-mediated growth arrest. In contrast, FasL suppressed proliferation of T cells in vitro that did not receive NKG2D costimulation. Similar observations with normal peripheral blood NKG2D(+)CD8(+) T cells demonstrated unrecognized NKG2D-mediated immune functions, whereby FasL release promotes tumor cell death and NKG2D costimulation prolongs T cell survival. These effects, beneficial in conditions of limited NKG2D ligand expression, may be counterweighed when massive expression and shedding of MIC occurs, such as in some late-stage tumors, that causes sustained NKG2D costimulation and population expansion of immunosuppressive T cells.
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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CD4-Positive T-Lymphocytes / chemistry
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Carcinoma / immunology
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Carrier Proteins / analysis
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Cytokines / metabolism
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Cytoplasmic Granules / metabolism
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Fas Ligand Protein
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GPI-Linked Proteins
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Gene Expression Regulation
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Histocompatibility Antigens Class I / analysis
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Humans
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Intercellular Signaling Peptides and Proteins
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Intracellular Signaling Peptides and Proteins
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Lymphocytes, Tumor-Infiltrating / chemistry
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Lymphocytes, Tumor-Infiltrating / immunology*
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Lymphocytes, Tumor-Infiltrating / metabolism
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Melanoma / immunology
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Membrane Glycoproteins / biosynthesis
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Membrane Glycoproteins / physiology*
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Membrane Proteins / analysis
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NK Cell Lectin-Like Receptor Subfamily K
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Neoplasms / immunology*
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Neoplasms / pathology
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Paracrine Communication / physiology*
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Receptors, Immunologic / analysis
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Receptors, Immunologic / physiology*
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Receptors, Natural Killer Cell
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Solubility
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Tumor Necrosis Factors / biosynthesis
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Tumor Necrosis Factors / physiology*
Substances
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Carrier Proteins
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Cytokines
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FASLG protein, human
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Fas Ligand Protein
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GPI-Linked Proteins
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Histocompatibility Antigens Class I
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Intercellular Signaling Peptides and Proteins
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Intracellular Signaling Peptides and Proteins
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KLRK1 protein, human
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MHC class I-related chain A
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Membrane Glycoproteins
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Membrane Proteins
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NK Cell Lectin-Like Receptor Subfamily K
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RAET1E protein, human
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RAET1G protein, human
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Receptors, Immunologic
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Receptors, Natural Killer Cell
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Tumor Necrosis Factors
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ULBP1 protein, human
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ULBP2 protein, human
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ULBP3 protein, human