Fas-ligand-mediated paracrine T cell regulation by the receptor NKG2D in tumor immunity.
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.
Groh
Veronika
V
Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, Washington 98109, USA.
Smythe
Kimberly
K
Dai
Zhenpeng
Z
Spies
Thomas
T
D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002277:Carcinoma / Q000276:immunology; D002352:Carrier Proteins / Q000032:analysis; D016207:Cytokines / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000378:metabolism; D053222:Fas Ligand Protein; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation; D015395:Histocompatibility Antigens Class I / Q000032:analysis; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016246:Lymphocytes, Tumor-Infiltrating / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D008545:Melanoma / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000502:physiology*; D008565:Membrane Proteins / Q000032:analysis; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D019899:Paracrine Communication / Q000502:physiology*; D011971:Receptors, Immunologic / Q000032:analysis / Q000502:physiology*; D055607:Receptors, Natural Killer Cell; D012995:Solubility; D048069:Tumor Necrosis Factors / Q000096:biosynthesis / Q000502:physiology*
D002352:Carrier Proteins; D016207:Cytokines; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; C488760:RAET1E protein, human; C488761:RAET1G protein, human; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D048069:Tumor Necrosis Factors; C423231:ULBP1 protein, human; C423230:ULBP2 protein, human; C423229:ULBP3 protein, human