When lymphocytes from DBA/2 mice are transferred to (C57BL X DBA/2)F1 (BDF1) mice, the ensuing graft-vs.-host reaction (GVHR) causes an autoimmune illness resembling human SLE. To examine the role of recipient T cells in this process, BDF1 mice were depleted of L3T4+ or Lyt-2+ cells by thymectomy followed by treatment with mAbs to L3T4 or Lyt-2. This produced sustained depletion of these T cell subsets. Subsequent grafting with parental DBA/2 lymphocytes produced autoimmune disease in mice depleted of L3T4+ cells and controls but not in mice depleted of Lyt-2+ cells. Analysis of blood lymphocytes 4 wk after donor cell transfer demonstrated that BDF1 recipients depleted of Lyt-2+ cells were virtually repopulated with donor T lymphocytes, compared with less than or equal to 35% donor cell engraftment in all other groups. Thus, recipient Lyt-2+ cells influence both host cell engraftment and autoimmunity during the parent-into-F1 GVHR.