Up-regulation of c-FLIPshort and Reduction of Activation-Induced Cell Death in T-cells from Patients with Type 1 Diabetes

AICD of T-cells is an efficient way of removing activated T-lymphocytes. In this study weinvestigated the molecular basis of AICD upon reactivation in peripheral T-lymphocytes from newlydiagnosed T1DM patients and age-matched healthy controls. In an in vitro model system, PHA-stimulatedT-cells, upon prolonged culture in IL-2, acquire a sensitive phenotype to Fas-mediated apoptosis.This phenomenon is less pronounced in T1DM T-cells. Moreover, the restimulation of activatedT-cells via TCR/CD3 and/or via CD28 inhibits Fas-mediated apoptosis in T1DM in comparison to controlT-cells. After Fas triggering, the generation of the active sub-units of caspase-8 is significantly reducedin T1DM T-cells restimulated via TCR/CD3 and/or CD28. In parallel, we found that the amountof c-FLIPshort protein is significantly increased in the DISC only in T1DM T-cells restimulated viaTCR/CD3 and via CD28. These data suggest that increased levels of c-FLIPshort may prevent recruitmentof pro-caspase-8 in T1DM CD3-treated T-cells and provide new insight into the molecular mechanismsof apoptosis resistance in stimulated T-cells from T1DM patients.