A narrow T cell receptor repertoire instructs thymic differentiation of MHC class Ib–restricted CD8+ regulatory T cells

Although most CD8+T cells are equipped to kill infected ortransformed cells, a subset may regulate immune responses and preserve self-tolerance. Here, we describe a CDS lineage that is instructed to differentiate into CDS T regulatory cells (Tregs) by a surprisingly restricted set of T cell receptors (TCRs) that recognize MHC-E (mouse Qa-1) and several dominant self-peptides. Recognition and elimination of pathogenic target cells that express these Qa-1-self-peptide complexes selectively inhibits pathogenic antibody responses without generalized immune suppression. Immunization with synthetic agonist peptides that mobilize CDS Tregs in vivo efficiently inhibit antigraft antibody responses and markedly prolong heart and kidney organ graft survival. Definition of TCR-dependent differentiation and target recognition by this lineage of CDS Tregs may open the way to new therapeutic approaches to inhibit pathogenic antibody responses.