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.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.