The potential role of suppressor T cells (T.) in the Induction of self-tolerance was investigated by eliminating I-J+ cells during ontogeny (I-J antigens are encoded by the I-I subregion of the murine major histocompatibility complex). To achieve this, F1 mice were exposed to anti-I-J antibodies via the transplacental route by mating B1O.A(3R) females, preimmunized with B1O.A(5R) cells, with CBA males. At 6 weeks of age, the offspring were injected with rat erythrocytes (RRBC) to induce erythrocyte autoantibodies. By comparison with agematched controls, T,-depleted mice produced siicantly higher titers of autoantibody, whereas there was no difference in the antibody response of the two groups to the foreign determinants on the RRBC. The selective increase in autoantibody production was mirrored at the clonal level by the appearance of self-reactive B-cell hybridomas after fusion of RRBC-immune spleen cells with the NS-1 cell line. On the other hand, when helper cell function of RRBC-primed cells was measured in a T-cell proliferative assay, Ts depletion in utero resulted in enhanced T-cell activity to nonself (RRBC) but not to self (mouse erythrocyte) determinants. Thus, helper T cells recognizing nonself determinants on RRBC appeared to be responsible for activating self-specific B cells, presumably through linked recognition of different epitopes on mouse erythrocytes. Taken together, these findings indicate that elimination of I-J+ cells during ontogeny can lead to the appearance and activation of "forbidden" B-cell clones and points to a central role for Ts in induction as well as maintenance of self-tolerance.A precise understanding of autoimmunity depends on identification ofthe mechanisms responsible for the induction and maintenance of self-tolerance. Despite substantial advances made in delineating the events underlying the development of tolerance to foreign antigens, a consensus has yet to be reached concerning the cellular basis of self-tolerance. Protagonists of the clonal deletion theory (1) and its more recent modifications (2) base their arguments for a repertoirepurging mechanism on the exquisite sensitivity of immature lymphocytes (e.g., pre-B-cells) to physiological concentrations of antigen (2). On the other hand, there are a number of experimental observations that are not compatible with a simple deletion model of self-tolerance but rather implicate the existence of active suppressor mechanisms capable of inhibiting autoimmune responses. For example, autoantigen binding B cells (3) and autoreactive T helper (Th) cells (4) have been demonstrated in healthy subjects, and it is rela-