Patients transplanted for the treatment of severe combined immunodeficiency (SCID) frequently develop a unique state of split lymphoid chimerism. Such patients have T cells of donor origin, and non-T cells which are predominantly or exclusively of host origin. We have studied the reactivity of engrafted donor T cells to host and/or donor antigens in 12 patients transplanted for SCID, focusing on the characteristics of the tolerance to host and/or donor MHC antigens observed in nine of these patients who were recipients of T-cell-depleted, haploidentical parental bone marrow. In both proliferative and cytolytic assays, engrafted, donor-derived T cells were shown to be selectively nonreactive to histoincompatible host cells VSports手机版. This tolerance could not be ascribed to cells with suppressive activity in the engrafted T-cell population. T cells from a subset of patients, however, exhibited proliferative but not cytolytic reactivity to donor peripheral blood mononuclear cells. The responding cells were shown to be donor-derived CD3+ cells and were predominantly reactive to B-cell fractions from the donor. Two patients who received transplants from each parent in sequence engrafted T cells from one parent and had non-T cells of host, paternal, and maternal origin. The engrafted T cells proliferated weakly to B cells from the other parent, but were tolerant in cytolytic assays. Donor anti-donor reactivity was seen only in haploidentical split chimeras who had not been treated with cytotoxic drugs prior to T-cell engraftment. This proliferative reactivity toward donor may be due to an absence of donor derived Ia+ antigen presenting cells resident in the thymus of SCID patients at the time when the T-cell repertoire is being shaped. .