Mice infected with mouse hepatitis virus, strain JHM (MHV-JHM), develop acute encephalitis or subacute or chronic demyelination. Clinical and pathological findings in mice with the subacute or chronic disease are similar to what is observed in patients with multiple sclerosis. These diseases are in large part immune-mediated, yet until now it has been difficult to determine the precise role of antigen-specific immune cells in the immunopathological process. A recently described technique using tetramers of major histocompatibility complex (MHC) molecules with bound peptide offers a powerful way to answer questions about the induction, propagation and specificity of the immune response. These soluble probes, which mimic antigenic peptides presented by APC, bind to specific T cell receptors and can thereby be used to identify epitope-specific T cells, even when these cells comprise only a minority of the T cells in lymphoid tissue or the inflammatory site. In previous work, the principal investigator and his colleagues identified MHC-specific CD4 and CD8 T cell epitopes recognized by T cells harvested from the brains and spinal cords of infected mice. This information, in conjunction with MHC/peptide tetramer technology, will be used to address specific issues involving individual antigen-specific cells in the inflamed CNS. In the first specific aim, the investigators will develop and validate MHC/peptide tetrameric probes for T cells recognizing MHC-specific H-2Db-, H-2 Kb-, and l-Ab-restricted epitopes. In the second specific aim, they will use these probes to trace the tissue localization, phenotype and antigen specificity of T cells during the induction and effector phases of the anti-MHV immune response in vivo.
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