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Systemic NKG2D Down-Regulation Impairs NK and CD8 T Cell Responses In Vivo¹

Katrin Wiemann^*, Hans-Willi Mittrücker, Ute Feger^*, Stefan A. Welte^*, Wayne M. Yokoyama, Thomas Spies, Hans-Georg Rammensee^* and Alexander Steinle^2,*

^* Department of Immunology, Institute for Cell Biology, Eberhard Karls University Tübingen, Tübingen, Germany; Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany; Howard Hughes Medical Institute, Division of Rheumatology, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, MO 63110; and Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA 98109

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.

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