Prolonged exposure to type-I IFN inhibits IL-10 signaling in memory and regulatory T cells: a new mechanism contributing to the development of autoimmune diseases (BA13P.130)

Abstract

Abstract Interleukin 10 (IL-10) is a fundamental immunoregulatory cytokine. Mice with memory T cells (Tmem)- or regulatory T cells (Treg)-specific depletion of the IL-10 receptor (IL-10R) develop fatal autoimmune diseases. However, no correlation is known between pathological conditions and altered IL-10 signaling in T cells. We investigated the influence of prolonged exposure to the supernatant of mouse maturing dendritic cells, exposed to LPS, on the integrity of the IL-10 signaling pathway in Tmem and Treg. Following 36-48h incubation, a block in phosphorylation of STAT3 in response to IL-10, but not in response to IL-6, was evident. This IL-10-specific unresponsiveness was not associated with lower IL-10R expression. Additionally, this inhibition was not induced by IL-6 or IL-1. Instead, incubation with IFN-β impaired IL-10 signaling in both Tmem and Treg. This effect was not blocked by AKT inhibition, suggesting a role for Jak/STAT or other IFN-β-initiated signaling pathways. In NOD mice, a model of human type-1 diabetes (T1D), diabetes development is linked to high levels of type-I interferons in pancreatic lymph nodes (PNC-LN). We analyzed the IL-10 response in T cells from spleen, PNC-LN, other LNs, and pancreata of NOD mice and discovered that starting at 4 weeks of age, Tmem and Treg in PNC-LN and pancreata display suppressed responses to IL-10. Overall, these data reveal a new molecular mechanism that controls the development of autoimmunity and the pathogenesis of T1D.