Functional Expression of Chemokine Receptor CCR5 on CD4 super(+) T Cells during Virus-Induced Central Nervous System Disease

Intracranial infection of C57BL/6 mice with mouse hepatitis virus (MHV) results in an acute encephalomyelitis followed by a demyelinating disease similar in pathology to the human disease multiple sclerosis (MS). CD4 super(+) T cells are important in amplifying demyelination by attracting macrophages into the central nervous system (CNS) following viral infection; however, the mechanisms governing the entry of these cells into the CNS are poorly understood. The role of chemokine receptor CCR5 in trafficking of virus-specific CD4 super(+) T cells into the CNS of MHV-infected mice was investigated. CD4 super(+) T cells from immunized CCR5 super(+/+) and CCR5 super(-/-) mice were expanded in the presence of the immunodominant epitope present in the MHV transmembrane (M) protein encompassing amino acids 133 to 147 (M133-147). Adoptive transfer of CCR5 super(+/+)-derived CD4 super(+) T cells to MHV-infected RAG1 super(-/-) mice resulted in CD4 super(+)-T-cell entry into the CNS and clearance of virus from the brain. These mice also displayed robust demyelination correlating with macrophage accumulation within the CNS. Conversely, CD4 super(+) T cells from CCR5 super(-/-) mice displayed an impaired ability to traffic into the CNS of MHV-infected RAG1 super(-/- ) recipients, which correlated with increased viral titers, diminished macrophage accumulation, and limited demyelination. Analysis of chemokine receptor mRNA expression by M133-147-expanded CCR5 super(-/-)-derived CD4 super(+) T cells revealed reduced expression of CCR1, CCR2, and CXCR3, indicating that CCR5 signaling is important in increased expression of these receptors, which aid in trafficking of CD4 super(+) T cells into the CNS. Collectively these results demonstrate that CCR5 signaling is important to migration of CD4 super(+) T cells to the CNS following MHV infection.