Systemic NKG2D down-regulation impairs NK and CD8 T cell responses in vivo.
The immunoreceptor NKG2D stimulates activation of cytotoxic lymphocytes upon engagement with MHC class I-related NKG2D ligands of which at least some are expressed inducibly upon exposure to carcinogens, cell stress, or viruses. In this study, we investigated consequences of a persistent NKG2D ligand expression in vivo by using transgenic mice expressing MHC class I chain-related protein A (MICA) under control of the H2-K(b) promoter. Although MICA functions as a potent activating ligand of mouse NKG2D, H2-K(b)-MICA mice appear healthy without aberrations in lymphocyte subsets. However, NKG2D-mediated cytotoxicity of H2-K(b)-MICA NK cells is severely impaired in vitro and in vivo. This deficiency concurs with a pronounced down-regulation of surface NKG2D that is also seen on activated CD8 T cells. As a consequence, H2-K(b)-MICA mice fail to reject MICA-expressing tumors and to mount normal CD8 T cell responses upon Listeria infection emphasizing the importance of NKG2D in immunity against tumors and intracellular infectious agents.
Department of Immunology, Institute for Cell Biology, Eberhard Karls University Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, Germany.
Katrin
K
Wiemann
Hans-Willi
HW
Mittrücker
Ute
U
Feger
Stefan A
SA
Welte
Wayne M
WM
Yokoyama
Thomas
T
Spies
Hans-Georg
HG
Rammensee
Alexander
A
Steinle
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D016466:CHO Cells; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D006224:Cricetinae; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006183:H-2 Antigens / Q000502:physiology; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D007113:Immunity, Innate / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D008088:Listeriosis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000502:physiology; D055607:Receptors, Natural Killer Cell
D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D015395:Histocompatibility Antigens Class I; C527086:Klrk1 protein, mouse; C099187:MHC class I-related chain A; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell