Mast cells contribute to autoimmune diabetes by releasing interleukin-6 and failing to acquire a tolerogenic IL-10 + phenotype

摘要

Abstract Mast cells (MCs) are innate immune cells that exert positive and negative immune modulatory functions capable to enhance or limit the intensity and/or duration of adaptive immune responses. Although MCs are crucial to regulate T cell immunity, their action in the pathogenesis of autoimmune diseases is still debated. Here we demonstrate that MCs play a crucial role in T1D pathogenesis so that their selective depletion in conditional MC knockout NOD mice protects them from the disease. MCs of diabetic NOD mice are overly inflammatory and secrete large amounts of IL-6 that favors differentiation of IL-17-secreting T cells at the site of autoimmunity. Moreover, while MCs of control mice acquire an IL-10+ phenotype upon interaction with FoxP3+ Treg cells, MCs of NOD mice do not undergo this tolerogenic differentiation. Our data indicate that overly inflammatory MCs unable to acquire a tolerogenic IL-10+ phenotype contribute to the pathogenesis of autoimmune T1D. Graphical abstract Display Omitted Highlights " We use conditional knockout NOD mice to deplete MCs at different checkpoints in Type 1 Diabetes pathogenesis. " A crucial role for MCs in autoimmune T1D is demonstrated. " Islet inflammation induces local recruitment of MCs in T1D. " MCs that contribute to T1D are overly inflammatory and fail to undergo tolerogenic maturation upon interaction with FoxP3 + Treg cells. " We provide mechanistic insights showing that MC secretion of cytokines/chemokines promotes T1D and favors Th17 cell recruitment and/or expansions. ]]>