A central role for CD4(+) T cells and RANTES in virus-induced central nervous system inflammation and demyelination

Infection of C57BL/6 mice with mouse hepatitis virus (MHV) results in a dem yelinating encephalomyelitis characterized by mononuclear cell infiltration and white matter destruction similar to the pathology of the human demyeli nating disease multiple sclerosis, The contributions of CD4(+) and CD8(+) T cells in the pathogenesis of the disease were investigated. Significantly less severe inflammation and demyelination were observed in CD4(-/-) mice t han in CD8(-/-) and C57BL/6 mice (P less than or equal to 0.002 and P less than or equal to 0.001, respectively). Immunophenotyping of central nervous system (CNS) infiltrates revealed that CD4(-/-) mice had a significant red uction in numbers of activated macrophages/microglial cells in the brain co mpared to the numbers in CD8(-/-) and C57BL/6 mice, indicating a role for t hese cells in myelin destruction. Furthermore, CD4(-/-) mice displayed lowe r levels of RANTES (a C-C chemokine) mRNA transcripts and protein, suggesti ng a role for this molecule in the pathogenesis of MEN-induced neurologic d isease. Administration of RANTES antisera to MEN-infected C57BL/6 mice resu lted in a significant reduction in macrophage infiltration and demyelinatio n (P less than or equal to 0.001) compared to those in control mice. These data indicate that CD4(+) T cells have a pivotal role in accelerating CNS i nflammation and demyelination within infected mice, possibly by regulating RANTES expression, which in turn coordinates the trafficking of macrophages into the CNS, leading to myelin destruction.