Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
CD8-Positive T-Lymphocytes / immunology*
-
CD8-Positive T-Lymphocytes / metabolism
-
CD8-Positive T-Lymphocytes / microbiology
-
CHO Cells
-
Cell Line, Tumor
-
Coculture Techniques
-
Cricetinae
-
Cytotoxicity, Immunologic / genetics
-
Down-Regulation / genetics
-
Down-Regulation / immunology*
-
Graft Rejection / genetics
-
Graft Rejection / immunology
-
H-2 Antigens / physiology
-
Histocompatibility Antigens Class I / biosynthesis
-
Histocompatibility Antigens Class I / genetics*
-
Histocompatibility Antigens Class I / physiology
-
Immunity, Innate / genetics
-
Killer Cells, Natural / immunology*
-
Killer Cells, Natural / metabolism
-
Killer Cells, Natural / microbiology
-
Listeriosis / genetics
-
Listeriosis / immunology
-
Listeriosis / pathology
-
Lymphocyte Activation / genetics
-
Lymphoma, T-Cell / genetics
-
Lymphoma, T-Cell / immunology
-
Lymphoma, T-Cell / pathology
-
Mice
-
Mice, Inbred C57BL
-
Mice, Inbred CBA
-
Mice, Knockout
-
Mice, Transgenic
-
NK Cell Lectin-Like Receptor Subfamily K
-
Receptors, Immunologic / antagonists & inhibitors*
-
Receptors, Immunologic / biosynthesis*
-
Receptors, Immunologic / physiology
-
Receptors, Natural Killer Cell
Substances
-
H-2 Antigens
-
H-2Kb protein, mouse
-
Histocompatibility Antigens Class I
-
Klrk1 protein, mouse
-
MHC class I-related chain A
-
NK Cell Lectin-Like Receptor Subfamily K
-
Receptors, Immunologic
-
Receptors, Natural Killer Cell