The proliferative responses of T cells, depleted of alloreactive cells, were tested upon stimulation by antigens presented on allogeneic antigen-presenting cells (APC). Restriction molecules involved in these responses were identified by inhibition of T cell proliferation with monoclonal antibodies against A(A alpha A beta) and E(E alpha E beta) molecules of the APC. The responses to all three antigens tested [Poly(Glu40Ala60) (GA), lactate dehydrogenase B (LDHB), and poly(Glu51, Lys34, Tyr15) (GLT)] were A plus E restricted when the allogeneic APC expressed both molecules, and only A restricted when the APC did not express cell surface E molecules. In contrast, when T cells and APC are syngeneic, the same antigens are recognized only in the context of either A molecules (GA and LDHB) or E molecules (GLT). The data indicate that the immune response gene control of these responses is not associated with either a failure of antigen presentation, or the lack of certain T cell specificities from the germ line repertoire, but probably with selective somatic elimination (tolerance) of certain clones from the T cell repertoire.