Specificity of human T cell clones reactive to immunodominant epitopes of myelin basic protein

AbstractSeveral recently discovered lines of evidence support the involvement of myelin basic protein (BP)‐specific T cells in multiple sclerosis (MS). To identify potentially relevant immunodominant T cell epitopes, human BP (Hu‐BP)‐reactive T cell lines were selected from MS and normal donors and tested for reactivity to cleavage fragments and synthetic peptides of Hu‐BP. The MS T cell lines responded to more Hu‐BP epitopes than did normal lines, showing biased recognition of the N terminal half of the molecule, and one region in the C terminal half, suggesting increased sensitization to BP. The MS lines also differed from normal lines in their decreased percentage of CD8 + cells. One hundred nine T cell clones isolated from these lines confirmed the reactivity pattern of the lines but did not reflect the mixed phenotype, since all but three clones tested were CD4+. T cell clones from HLA‐DR2 homozygous donors responded to a variety of epitopes, indicating that this molecule was permissive in its ability to restrict T cell responses. Other epitopes, including the immunodominant 149‐170 sequence, were restricted by several different major histocompatibility complex (MHC) molecules from both MS and normal donors. T cell receptor (TCR) V gene products could be identified on six of 38 clones tested using monoclonal antibodies. From one HLA‐DR2 homozygous donor, four of eight clones utilized Vβ5.2 in response to different BP epitopes, providing initial support for the preferential use of a limited set of V region genes in the human response io BP. Preferential TCR V gene use in MS patients would provide the rationale to regulate selectively BP‐reactive T cells through immunity directed at the TCR and thus test for the first time the hypothesis that BP‐reactive T cells play a critical role in the pathogenesis of MS.