Effector T Cell Resistance to Suppression and STAT3 Signaling during the Development of Human Type 1 Diabetes

Dysregulation of regulatory T cell (Treg)-mediated suppression and, in particular, resistance of CD4⁺ effector T cells (Teffs) to suppression have been implicated in the pathogenesis of human type 1 diabetes (T1D). However, the mechanistic basis behind this resistance and the time frame during which it develops in relation to the onset of clinical T1D remain unclear. In this study, we analyzed the capacity of peripheral blood Teffs isolated both from patients with T1D and from prediabetic at-risk subjects positive for multiple diabetes-associated autoantibodies (AAb⁺) to be suppressed by Tregs. Because STAT3 activation through IL-6 has previously been implicated in mediating Teff resistance, we also investigated the surface expression of IL-6R as well as IL-6- and TCR-mediated phosphorylation of STAT3 in T cells from our study subjects. Teff resistance to suppression was observed both in patients with newly diagnosed and long-standing T1D but not in AAb⁺ subjects and was shown to be STAT3 dependent. No alterations in IL-6R expression or IL-6-mediated STAT3 activation were observed in T cells from patients with T1D or AAb⁺ subjects. However, faster STAT3 activation after TCR stimulation without concomitant increase in IL-6 expression was observed in T cells from patients with T1D. These experiments suggest that Teff resistance in T1D patients is STAT3 dependent but not directly linked with the capacity of Teffs to produce or respond to IL-6. In conclusion, Teff resistance to Treg-mediated suppression is likely a feature of disease progression in human T1D and can potentially be targeted by immune therapies that block STAT3 activation.