The scurfy (sf) murine mutation results in a rapidly fatal lymphoproliferative disease, causing death by 26 days. Mature CD4+ T cells which tested hyperresponsive to T cell receptor (TCR) stimulation are involved. When sf was bred onto a transgenic line (DO11.10) in which 75 - 95 % of the T cells express TCR for ovalbumin (OVA) 323 - 339, sf / Y OVA mice had prolonged lifespans and less severe clinical symptoms compared to controls. However, sf / Y OVA mice eventually developed disease and died with manifestations similar to those of the original sf strain. The Rag1 knockout (KO) mouse, which cannot produce mature T (or B) cells without the addition of functional transgenes, was chosen for further breeding. The combination of Rag1 KO, the OVA transgene, and sf produced mice with 100 % of their mature DO11.10 alpha beta T cells reactive strictly to OVA peptide. None of these Rag1 - / - sf / Y OVA mice developed the scurfy disease. They retained central deletion capability in vivo, but demonstrated an altered in vitro response to OVA peptide. These results indicate that mice without TCR for endogenous antigens do not develop scurfy symptoms, and are consistent with the hypothesis that the sf mutation requires antigen stimulation to manifest disease, perhaps via altered TCR sensitivity.