Although autoreactive T cells are thought to play a prominent role in autoimmune disease in MRL-lprllpr mice, it has been difficult to directly determine if autoreactive T cells escape from the thymus and react with self-antigens in the periphery. Defective expression of the Fas apoptosis antigen in MRL-lpr/lpr mice results from the insertion of the ETn retrotransposon. The. fas defect can be partially corrected in CD2-fas transgenic mice in which the expression of fas is corrected in T cells. To identify a possible defect in clonal deletion or clonal anergy induction of auto-specific T cells, we have studied C51BL/6-lpr/lpr transgenic mice that express TcR genes that recognize a known self-antigen, the male H-Y antigen. In addition, we have analyzed clonal deletion and tolerance induction after neonatal tolerance induction and superantigen-induced arthritis with the class IIMHC reactive superantigen staphylococcal enterotoxin B (SEB) in Vβ38 TcR transgenic and non-transgenic MRL-lpr/lpr mice. Neonatal tolerance induction to SEB was normal in Iprilpr mice. However, over time a loss of tolerance (thymic or peripheral) was observed in Iprilpr mice but not in +plus; TcR transgenic mice. This defect in lpr/lpr mice was thymic-dependent and was due to increased CD28/CTLA4 signaling. These results suggest that an apoptosis defect involving both thymocytes and peripheral lymphoid cells leads to autoimmune disease in Iprilpr mice. The challenge in the future will be to determine the role of defective apoptosis in other autoimmune diseases. © 1994 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.