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.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Down-Regulation/immunology , Histocompatibility Antigens Class I/genetics , Killer Cells, Natural/immunology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Immunologic/biosynthesis , Animals , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/microbiology , CHO Cells , Cell Line, Tumor , Coculture Techniques , Cricetinae , Cytotoxicity, Immunologic/genetics , Down-Regulation/genetics , Graft Rejection/genetics , Graft Rejection/immunology , H-2 Antigens/physiology , Histocompatibility Antigens Class I/biosynthesis , Histocompatibility Antigens Class I/physiology , Immunity, Innate/genetics , 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/physiology , Receptors, Natural Killer CellABSTRACT
Human cytomegalovirus (HCMV) has evolved a multitude of molecular mechanisms to evade the antiviral immune defense of the host. Recently, using soluble recombinant molecules, the HCMV UL16 glycoprotein was shown to interact with some ligands of the activating immunoreceptor NKG2D and, therefore, may also function as a viral immunomodulator. However, the role of UL16 during the course of HCMV infection remained unclear. Here, we demonstrate that HCMV infection of fibroblasts induces expression of all known NKG2D ligands (NKG2DL). However, solely MICA and ULBP3 reach the cellular surface to engage NKG2D, whereas MICB, ULBP1 and ULBP2 are selectively retained in the endoplasmic reticulum by UL16. UL16-mediated reduction of NKG2DL cell surface density diminished NK cytotoxicity. Thus, UL16 functions by capturing activating ligands for cytotoxic lymphocytes that are synthesized in response to HCMV infection.