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.