Repertoire requirements of CD4+ T cells that prevent spontaneous autoimmune encephalomyelitis.

Spontaneous experimental autoimmune encephalomyelitis arises in 100% of mice exclusively harboring myelin basic protein-specific T cells, and can be prevented by a single injection of CD4+ T cells obtained from normal donors. Given the powerful regulatory effect of the transferred T cells, we further investigated their properties, and, in particular, their repertoire requirements. Transfer of monoclonal OVA-specific CD4+ T cells did not confer protection from disease even when present at very high proportions (about 80% of total lymphocytes). Lack of protection was also evident after immunization of these animals with OVA, indicating that not just any postthymic CD4+ T cells has the potential to become regulatory. However, protection was conferred by cells bearing limited TCR diversity, including cells expressing a single Valpha4 TCR chain or cells lacking N nucleotides. We also investigated whether coexpression of the myelin basic protein-specific TCR with another TCR in a single cell would alter either pathogenesis or regulation. This was not the case, as myelin basic protein-specific/OVA-specific recombinase activating gene-1-/- double TCR transgenic mice still developed experimental autoimmune encephalomyelitis spontaneously even after immunization with OVA. Based on this evidence, we conclude that CD4+ T regulatory cells do not express canonical TCRs and that the altered signaling properties brought about by coexpression of two TCRs are not sufficient for the generation of regulatory T cells. Instead, our results indicate that regulatory T cells belong to a population displaying wide TCR diversity, but in which TCR specificity is central to their protective function.