The role of B cells and gammadelta T cells in the pathogenesis of mouse hepatitis virus induced demyelination

Mice infected with the neurotropic coronavirus, mouse hepatitis virus, strain JHM, develop immune-mediated acute and chronic demyelinating diseases. In one experimental model, C57Black/6 mice are infected at ten days of age with JHM and nursed on JHM-immunized dams. These mice develop a chronic demyelinating encepahlaomyelitis that is characterized by mutations in the immunodominant CD8 T cell epitope within the virus. These mutations lead to an ineffective cellular immune response. C57Black/6 mice mount a minimal antibody response within the central nervous system to this virus. This lack of an antibody response appears to be unique to chronic demyelination induced by JHM, as mice infected with an attenuated strain of JHM mount a robust antibody response to JHM within the central nervous system. This defect in the antibody response also does not appear to be the result of JHM-induced killing of B cells or B cell precursors, or by general modulation of the immune response. BALB/b mice, which present the same CD8 T cell epitopes as do C57Black/6 mice, do not develop mutations in the immunodominant epitope, suggesting that the antibody response may prevent the emergence of these variants. This was demonstrated in C57Black/6 mice by administration of anti-JHM antibody, which abrogated clinical disease and reduced the frequency of epitope escape variants.; One interesting historical exception to the observation that JHM-induced demyelination is T cell mediated was the finding that athymic mice develop demyelination despite the lack of CD4 and CD8 T cells. Herein, I showed that this process is mediated by a novel cellular agent of demyelination, gammadelta T cells. Depletion of these cells abrogated demyelination in athymic mice and mice genetically deficient in alphabeta T cells. Demyelination mediated by gammadelta T cells, similar to CD8 T cells, requires interferon-gamma, and macrophage-microglia infiltration into the white matter is dependent on the production of this cytokine. While it remains unknown whether these cells recognize JHM or JHM-derived antigens, the demyelination induced by gammadelta T cells is in part dependent on NKG2D, an activating receptor on natural-killer cells. This is the first description of a role for the NKG2D molecule in virus-induced demyelination.