There is now a substantial body of data demonstrating the abilities of synthetic peptides and peptide analogues to inhibit the auto-and alloimmune response in vitro and in vivo. We have studied the immunomodulatory role of synthetic peptides derived from highly conserved regions of the class II MHC α chain. These MHC-derived peptides inhibit the rat, human, and mouse mixed lymphocyte response (MLR), proliferation to autoantigen, cytokine production, and cytolytic T lymphocyte (CTL) generation. Our studies demonstrated that the inhibitory effect of the MHC class II nonpolymorphic peptides is mediated through the induction of apoptosis in APCs via a nonclassic caspase-independent pathway. In addition, T lymphocytes initially stimulated in the presence of HLA-DQA1 are rendered hyporesponsive to subsequent stimuli. Immunomodulation by HLA-DQA1 was effective in vivo because it prevented both the priming and the effector function of primed allogeneic T cells in a murine DTH model. Our data demonstrate that peptides derived from highly conserved regions of the class II MHC α chain can alter T-lymphocyte immune responses both in vitro and in vivo. These results have important implications for the development of a novel therapy for immune mediated diseases.