Sustained localized expression of ligand for the activating NKG2D receptor impairs natural cytotoxicity in vivo and reduces tumor immunosurveillance.
Upregulation of the inducible gene products MICA (human) and Rae-1 (mouse) may promote tumor surveillance and autoimmunity by engaging the activating receptor NKG2D on natural killer (NK) cells and T cells. Nevertheless, sustained expression of MICA by tumors can also elicit NKG2D downregulation, perhaps indicating 'immunoevasion'. Investigating this paradox, we report here that constitutive Rae-1epsilon transgene expression in normal epithelium elicited local and systemic NKG2D downregulation, generalized but reversible defects in NK cell-mediated cytotoxicity and mild CD8(+) T cell defects. The extent of NKG2D downregulation correlated well with the incidence and progression of cutaneous carcinogenesis, emphasizing the utility of NKG2D as a marker of tumor resistance. Thus, NKG2D engagement is a natural mediator of immunosurveillance, which can be compromised by locally sustained ligand expression but potentially restored by innate immune activation.
Oppenheim
David E
DE
Peter Gorer Department of Immunobiology, Guy's King's St. Thomas' School of Medicine, King's College, Guy's Hospital Campus, London SE1 9RT, UK.
Roberts
Scott J
SJ
Clarke
Sarah L
SL
Filler
Renata
R
Lewis
Julie M
JM
Tigelaar
Robert E
RE
Girardi
Michael
M
Hayday
Adrian C
AC
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002277:Carcinoma / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004198:Disease Susceptibility; D015536:Down-Regulation; D005260:Female; D007157:Immunologic Surveillance; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055655:NK Cell Lectin-Like Receptor Subfamily K; D010212:Papilloma / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D011971:Receptors, Immunologic / Q000276:immunology* / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D012878:Skin Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate; D047368:Tumor Burden
C527085:KLRK1 protein, human; C527086:Klrk1 protein, mouse; D008024:Ligands; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; C491219:Raet1a protein, mouse; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate