Disruption of the STAT4 signaling pathway protects from autoimmune diabetes while retaining antiviral immune competence

The role of the STAT4 signaling pathway in autoimmune diabetes was investig ated using the rat insulin promoter lymphocytic choriomeningitis virus mode l of virally induced autoimmune diabetes. Abrogation of STAT4 signaling sig nificantly reduced the development of CD4(+)-T cell-dependent but not CD4()-T cell-independent diabetes, illustrating the fine-tuned kinetics involve d in the pathogenesis of autoimmunity, Hen-ever, the absence of STAT4 did n ot prevent the generation of autoreactive Th1/Tc1 T cell responses, as well as protective antiviral immunity, Protection from insulin-dependent diabet es mellitus was associated with decreased numbers of autoreactive CTL precu rsors in the pancreas and the spleen and a general as well as Ag-specific r eduction of IFN-gamma secretion by T lymphocytes. A shift from Th1 to Th2 T cell immunity was not observed. Hence, our results implicate both CTL and cytokines in beta cell, destruction. Selective inhibition of the STAT4 sign al transduction pathway might constitute a novel and attractive approach to prevent clinical insulin-dependent diabetes mellitus in prediabetic indivi duals at risk.