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Department of Microbiology and Molecular Genetics, University of California, Los Angeles, CA 90095
Autoimmune diseases can result from the breakdown of regulation and subsequent activation of self-antigenic determinant-reactive T cells. During the evolution of the autoimmune response to myelin basic protein (MBP) in B10.PL mice, several distinct T cell populations expand: the effectors mediating experimental autoimmune encephalomyelitis (EAE) are MBP-reactive, CD4+, and predominantly TCR Vß8.2+; in addition, at least two regulatory populations can be detected—one comprised of Vß14+ CD4 T cells, reactive to a framework region 3 determinant on the Vß8.2 chain, and a second that is CD8+ and reactive to another Vß8.2 determinant. The combined action of these two regulatory cell types controls disease-causing effectors, resulting in spontaneous recovery from disease. In this report, we reveal that the cytokine secretion pattern of TCR peptide-specific regulatory CD4 T cells can profoundly influence whether a type 1 or type 2 population predominates among MBP-specific CD4 effectors. The priming of type 1 regulatory T cells results in deviation of the Ag-specific effector T cell population in a type 2 direction and protection from disease. In contrast, induction of type 2 regulatory T cells results in exacerbation of EAE, poor recovery, and an increased frequency of type 1 effectors. Thus, the encephalitogenic potential of the MBP-reactive effector population is crucially and dominantly influenced by the cytokine secretion phenotype of regulatory CD4 T cells. These findings have important implications in understanding peripheral tolerance to self-Ags as well as in the design of TCR-based therapeutic approaches.
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