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

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 gamma interferon (IFN-gamma) 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. The immunophenotyping of infiltrating cells revealed that NKG2D was expressed on approximately 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 the generation of virus-specific CD8(+) T cells, and the expression of IFN-gamma was not affected. However, cytotoxic T-lymphocyte (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 virus-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.
AuthorsKevin B Walsh, Lewis L Lanier, Thomas E Lane
JournalJournal of virology (J Virol) Vol. 82 Issue 6 Pg. 3031-44 (Mar 2008) ISSN: 1098-5514 [Electronic] United States
PMID18160433 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • KLRK1 protein, human
  • Klrk1 protein, mouse
  • NK Cell Lectin-Like Receptor Subfamily K
  • Receptors, Immunologic
  • Receptors, Natural Killer Cell
Topics
  • Animals
  • CD8-Positive T-Lymphocytes (immunology)
  • Cell Line
  • Cytotoxicity, Immunologic
  • Encephalitis, Viral (immunology, pathology)
  • Flow Cytometry
  • Hepatitis, Viral, Animal (immunology)
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • NK Cell Lectin-Like Receptor Subfamily K
  • Receptors, Immunologic (metabolism, physiology)
  • Receptors, Natural Killer Cell
  • Signal Transduction

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