CD4+ T cell response in the central nervous system in a virus model of multiple sclerosis

Intracerebral injection of Theiler's murine encephalomyelitis virus (TMEV) into susceptible strains of mice results in a chronic, progressive immune-mediated demyelinating disease of the central nervous system that has many clinical and histopathological similarities to human multiple sclerosis (MS). It is suggested that the CNS viral persistence and the ensuing inflammatory CD4 + T response contribute to the demyelinating disease in susceptible mice like SJL/J. It has also been proposed that CD4+ T cells may contribute to protection in resistant C57BL/6 mice but the mechanism remains unclear. To correlate the CNS-infiltrating CD4+ T cell response with susceptibility to TMEV-induced demyelinating disease in susceptible and resistant mice, we analyzed the levels, function and nature of infiltrating CD4+ T cells in these two strains.; As compared to resistant mice, susceptible mice have higher levels of CNS-infiltrating CD4+ T cells. However, in contrast to resistant mice, a very small proportion of these CD4+ T cells were found to be TMEV capsid-specific. Additionally, CNS of SJL/J mice have significantly higher levels of IL-10 producing Th2 cells during acute infection. Low anti-viral CD4+ T cell responses in SJL/J mice are likely due to lower costimulatory molecule (CD80, CD86 and CD40) expression on CNS antigen presenting microglial cells. Hence, low anti-viral Th1 response and the presence of IL-10 in the CNS likely delays viral clearance in SJL/J mice leading to demyelinating disease.; Using congenic strains (with different disease susceptibilities) that differ in only MHC class I, H-2D locus we show that on a background of a diverse immune response, CNS-infiltrating CD4+ and CD8+ T cell populations show antigen driven clonal expansion with the persistence of TMEV-specific CD4+ T cells in the CNS of susceptible strains. It appears that the resistant H-2D locus downregulates the expansion of certain potentially pathogenic CD4+ T cells thus influencing susceptibility.; Finally, we have successfully generated and used MHC class II-peptide multimers to track pathogenic autoantigen (myelin proteolipid protein, PLP)-specific CD4+ T cells in the CNS and immune organs in an autoimmune model of MS. Using this tool we show that PLP-specific cells accumulate and functionally mature in the CNS during disease progression.