A defect in central tolerance in NOD mice.

The predisposition of nonobese diabetic (NOD) mice to develop autoimmune disease is usually attributed to defects in peripheral tolerance mechanisms. Here, evidence is presented that NOD mice display a defect in central tolerance (negative selection) of thymocytes. Impaired central tolerance in NOD mice was most prominent in a population of semi-mature thymocytes found in the medulla. The defect was apparent in vivo as well as in vitro, was independent of IAbetag7 expression and affected both Fas-dependent and Fas-independent pathways of apoptosis; for Fas-dependent apoptosis, the defective tolerance of NOD thymocytes correlated with the strong T cell receptor-mediated up-regulation of caspase 8-homologous FLICE (Fas-associated death-domain-like interleukin 1beta-converting enzyme)-inhibitory protein. In light of these findings, disease onset in NOD mice may reflect defects in central as well as peripheral tolerance.