Although autoreactive T cells are thought to play a prominent role in autoimmune disease in MRL-lpr/lpr mice, it has been difficult to directly determine if autoreactive T cells escape from the thymus and react with self-antigens in the periphery. To identify a possible defect in clonal deletion or clonal anergy induction of auto-specific T cells, we have studied C57BL/6-lpr/lpr transgenic mouse expressing TCR genes that recognize a known self-antigen, the male H-Y antigen and analyzed clonal deletion and tolerance induction after neonatal tolerance induction with the class II MHC reactive superantigen staphylococcal enterotoxin B (SEB) in Vβ8 TCR transgenic and non-transgenic MRL-lpr/lpr mice. In lpr/lpr mice, the main defect was a thymic-dependent loss of self-tolerance by auto-specific T cells and also a small defect of clonal deletion of autoreactive thymocytes. Defective expression of the Fas apoptosis antigen results from the insertion of the ETn retrotransposon. The fas defect can be partially corrected in TCR-β TCR transgenic mice in which accelerated T cell development prevents the lymphoproliferative disease and in CD2-fas transgenic mice in which fas expression is corrected in T cells. These results suggest that expression of the TCR-β, fas and retrovirus genes are coregulated during early thymocyte development, most likely by common enhancer transcription factors. © 1994 Academic Press.