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J. Virol. doi:10.1128/JVI.02033-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

NKG2D signaling enhances cytolytic activity by virus-specific CD8⁺ T cells: Evidence for a protective role in viral-induced encephalitis

Department of Molecular Biology and Biochemistry, and Center for Immunology, University of California, Irvine 92697; Department of Microbiology and Immunology, and Cancer Research Institute, University of California, San Francisco 94143

^* To whom correspondence should be addressed. Email: tlane{at}uci.edu.

	Abstract

Inoculation with the neurotropic JHM strain of mouse hepatitis virus (JHMV) into the central nervous system (CNS) of mice results in an acute encephalitis associated with an immune-mediated demyelinating disease. During acute disease, infiltrating CD8⁺ T cells secrete IFN- that controls replication in oligodendrocytes, while infected astrocytes and microglia are susceptible to perforin-mediated lysis. The present study was undertaken to reveal the functional contributions of the activating NKG2D receptor in host defense and disease following JHMV infection. NKG2D ligands RAE-1, MULT1, and H60 were expressed within the CNS following JHMV infection. Immunophenotyping infiltrating cells revealed that NKG2D was expressed on 90% of infiltrating CD8⁺ T cells during acute and chronic disease. Blocking NKG2D following JHMV infection resulted in increased mortality that correlated with increased viral titers within the CNS. Anti-NKG2D treatment did not alter T cell infiltration into the CNS or generation of virus-specific CD8⁺ T cells, nor was expression of IFN- affected. However, CTL activity was dependent on NKG2D expression because anti-NKG2D treatment resulted in a dramatic reduction in lytic activity by virus-specific CD8⁺ T cells. Blocking NKG2D during chronic disease did not affect either T cell or macrophage infiltration or the severity of demyelination, indicating that NKG2D does not contribute to viral-induced demyelination. These findings demonstrate a functional role for NKG2D in host defense during acute viral encephalitis by selectively enhancing CTL activity by infiltrating virus-specific CD8⁺ T cells.