Type 1 diabetes (T1D) is an autoimmune disease caused by T cell-mediated destruction of insulin-producing beta cells of the pancreas. The “fertile field” hypothesis of T1D proposes that, in a genetically predisposed individual, an inflamed environment prompts the organ towards autoimmunity. In this context, the protective role of the regulatory cytokine IL-10 remains unclear and somewhat controversial. In this study, we tested whether chronic and localized accumulation of type-I interferons (TI-IFNs) creates a “fertile field” that releases diabetogenic T cells from IL-10 mediated regulation and prompts T1D development. In vitro incubation of mouse T cells with IFN-β induces a dramatic defect in the production of phospho-STAT3 in response to IL-10 (but not in response to IL-6, that shares the same signaling pathway). This resulted in prevention of upregulation of IL-10 induced genes. This altered signaling was NOT caused by reduction of IL-10 receptor expression, nor by induction of SOCS-1 or 3. Instead, microarray analysis suggested a novel role for the transcription factor STAT1. IFN-β increases STAT1 levels causing a reversal of the STAT1/STAT3 protein ratio in T cells, ultimately favoring a competitive role of STAT1. In agreement, STAT1-KO T cells exposed to IFN-β did not show any defect in IL-10 signaling. In diabetes-prone NOD mice we discovered a persistent reduction of IL-10 signaling in T cells of pancreatic and mesenteric lymph nodes (but not in T cells of other lymphoid tissues), correlating with the reported aberrant and localized accumulation of TI-IFNs in these mice. Early treatment of NOD mice with an IFNRA blocking antibody (that delays the onset and reduces the incidence of T1D) showed a clear restoration of IL-10 signaling. Overall, these data reveal a previously unknown molecular interplay between IL-10 and TI-IFNs that, if thoroughly elucidated, could reveal a novel target of intervention to enhance the efficacy of T1D immunotherapies.
M. Iglesias Lozano: None. M. Chicco: None. D.A. Bibicheff: None. G. Brandacher: None. G. Raimondi: None.