The genetic basis and familial clustering of autoimmunity suggest that common phenotypic traits predispose individuals to disease. We found a hyporesponsive T-cell phenotype that was shared by all autoimmune-prone mouse and rat strains tested, including MRL, nonobese diabetic (NOD), NZB, NZW, NZB/W F1, SJL and SWR mice, as well as DA and BB rats, but was not evident in nonautoimmune-prone rodents. This T-cell intrinsic, age-independent hyporesponsiveness is measured as an increased activation threshold for upregulation of activation markers upon T-cell receptor (TCR) cross-linking both in vitro and in vivo. Inefficient deletion of CD4 and CD8 single-positive, heat stable antigen (HSA)hi medullary thymocytes was also observed in hyporesponsive donors. We interpret these data to suggest that increased TCR-mediated signalling thresholds in autoimmune-prone individuals may contribute to the escape of autoreactive thymocytes from negative selection.