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Journal of Virology, January 2003, p. 191-198, Vol. 77, No. 1
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.1.191-198.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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

Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697-3900

Received 26 July 2002/ Accepted 25 September 2002

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⁺ 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⁺ T cells into the CNS of MHV-infected mice was investigated. CD4⁺ T cells from immunized CCR5^+/+ and CCR5^-/- 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^+/+-derived CD4⁺ T cells to MHV-infected RAG1^-/- mice resulted in CD4⁺-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⁺ T cells from CCR5^-/- mice displayed an impaired ability to traffic into the CNS of MHV-infected RAG1^-/- recipients, which correlated with increased viral titers, diminished macrophage accumulation, and limited demyelination. Analysis of chemokine receptor mRNA expression by M133-147-expanded CCR5^-/--derived CD4⁺ 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⁺ T cells into the CNS. Collectively these results demonstrate that CCR5 signaling is important to migration of CD4⁺ T cells to the CNS following MHV infection.