A defect in central tolerance in NOD mice

The predisposition of nonobese diabetic (NOD) mice to develop autoimmune di sease is usually attributed to defects in peripheral tolerance mechanisms. Here, evidence is presented that NOD mice display a defect in central toler ance (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 indep endent of IA beta (g7) expression and affected both Fas-dependent and Fas-i ndependent pathways of apoptosis; for Fas-dependent apoptosis, the defectiv e tolerance of NOD thymocytes correlated with the strong T cell receptor-me diated up-regulation of caspase 8-homologous FLICE (Fas-associated death-do main-like interleukin I beta -converting enzyme)-inhibitory protein. In lig ht of these findings, disease onset in NOD mice may reflect defects in cent ral as well as peripheral tolerance.