Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation.
Engagement of the NKG2D receptor by tumour-associated ligands may promote tumour rejection by stimulating innate and adaptive lymphocyte responses. In humans, NKG2D is expressed on most natural killer cells, gammadelta T cells and CD8alphabeta T cells. Ligands of NKG2D include the major histocompatibility complex class I homologues MICA and MICB, which function as signals of cellular stress. These molecules are absent from most cells and tissues but can be induced by viral and bacterial infections and are frequently expressed in epithelial tumours. MIC engagement of NKG2D triggers natural killer cells and costimulates antigen-specific effector T cells. Here we show that binding of MIC induces endocytosis and degradation of NKG2D. Expression of NKG2D is reduced markedly on large numbers of tumour-infiltrating and matched peripheral blood T cells from individuals with cancer. This systemic deficiency is associated with circulating tumour-derived soluble MICA, causing the downregulation of NKG2D and in turn severe impairment of the responsiveness of tumour-antigen-specific effector T cells. This mode of T-cell silencing may promote tumour immune evasion and, by inference, compromise host resistance to infections.
Groh
Veronika
V
Fred Hutchinson Cancer Research Center, Clinical Research Division, 1100 Fairview Avenue North, Seattle, Washington 98109, USA. vgroh@fhcrc.org
Wu
Jennifer
J
Yee
Cassian
C
Spies
Thomas
T
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D012995:Solubility; D014407:Tumor Cells, Cultured
D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; D008024:Ligands; C099187:MHC class I-related chain A; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009363:Neoplasm Proteins; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell