A Central Role for CD4⁺T Cells and RANTES in Virus-Induced Central Nervous System Inflammation and Demyelination

Abstract

Infection of C57BL/6 mice with mouse hepatitis virus (MHV) results in a demyelinating encephalomyelitis characterized by mononuclear cell infiltration and white matter destruction similar to the pathology of the human demyelinating 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 than in CD8(-/-) and C57BL/6 mice (P < or = 0.002 and P < or = 0.001, respectively). Immunophenotyping of central nervous system (CNS) infiltrates revealed that CD4(-/-) mice had a significant reduction in numbers of activated macrophages/microglial cells in the brain compared to the numbers in CD8(-/-) and C57BL/6 mice, indicating a role for these cells in myelin destruction. Furthermore, CD4(-/-) mice displayed lower levels of RANTES (a C-C chemokine) mRNA transcripts and protein, suggesting a role for this molecule in the pathogenesis of MHV-induced neurologic disease. Administration of RANTES antisera to MHV-infected C57BL/6 mice resulted in a significant reduction in macrophage infiltration and demyelination (P < or = 0.001) compared to those in control mice. These data indicate that CD4(+) T cells have a pivotal role in accelerating CNS inflammation 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.