I mmune T cells proliferate in response to antigen that is recognized in association with self-Ia determinants. T cells from a patient with severe combined immunodeficiency that has been successfully reconstituted with haplotype-mismatched, maternal bone marrow were studied in an attempt to understand the development of Ia restriction of antigen recognition in man. All the patient's T cells were of maternal origin as determined by HLA typing. The patient received a series of three immunizations with tetanus toxoid (TT) antigen between the 6th and 14th week posttransplant. TT-specific T cell lines were established from the patient's peripheral blood at 6 and 8 mo posttransplantation and were maintained in culture in the presence of irradiated monocytes from the patient, TT antigen, and interleukin-2. HLA typing of the two T cell lines revealed them to be exclusively of donor origin. Both T cell lines could proliferate to TT in the presence of monocytes derived from either the patient's mother or father. In contrast, a TT-specific T cell line obtained from the patient's mother proliferated to TT in the presence of autologous monocytes, but not in the presence of monocytes derived from the patient's father. Studies using monocytes from a panel of HLA-typed donors indicated that the patient's T cell lines proliferated to TT in the presence of monocytes that expressed the paternal DR antigen (HLA-DR4) inherited by the patient but not in the presence of monocytes that expressed the paternal DR antigen (HLA-DR1) not inherited by the patient or in the presence of monocytes bearing irrelevant DR antigens. Monocytes that expressed either one of the two maternal DR antigens (HLA-DR3 and DR5) could support the proliferation of the patient's T cell lines in response to TT antigen. HLA typing of the patient's monocytes at 6 mo post-transplant revealed only recipient HLA-DR antigens (HLA-DR3 and DR4). At 12 mo posttransplant, the patient's monocytes expressed recipient HLA-DR antigens as well as the non-shared HLA-DR5 antigen of donor origin. The results of the present study indicate that T cells of human bone marrow chimera recognized antigen in the context of Ia determinants of recipient origin. The apparent recognition of antigen by the chimera's T cells in the context of donor Ia determinants that were not shared with the recipient is discussed.