Antiviral responses are associated with triggering type 1 diabetes (T1D) including the synthesis of reactive oxygen species, proinflammatory cytokines, and autoreactive T cell activation. We previously demonstrated that Coxsackievirus B3 (CVB3) infection of Non-Obese Diabetic (NOD) mice accelerates T1D, partly due to the expression of melanoma differentiation-associated protein 5 (MDA5) antiviral sensor. Genetic mutations within human IFIH1, the gene encoding MDA5, are correlated with T1D susceptibility potentially due to increased IFN-α/β synthesis. However, the role of MDA5 in immune cell activation during T1D is unknown. By utilizing mice that lack (NOD.Ifih1KO) or contain a deletion within the helicase 1 domain of MDA5 (NOD.Ifih1ΔHel1), we can test the hypothesis that reduced MDA5 signaling delays T1D by decreasing IFN-α/β synthesis and debilitating islet-infiltrating macrophage and T cell effector responses. We observed that NOD and NOD.Ifih1KO mice develop T1D similarly, but NOD.Ifih1ΔHel1 were significantly protected from spontaneous and CVB3-accelerated T1D. During spontaneous T1D at 12 weeks of age, pancreatic macrophages from NOD.Ifih1ΔHel1 mice have a significant reduction in MHC-II (∼41%) and CD86 (∼43%) expression compared to NOD and NOD.Ifih1KO mice. CVB3-infected NOD.Ifih1ΔHel1 mice exhibited a significant decrease in pancreatic IFN-α (∼54%) and IFN-β (∼67%) synthesis at day 3 post-infection compared to NOD mice. Pancreatic NOD.Ifih1ΔHel1 CD4 and CD8 T cells had reduced T cell activation via CD25 (∼76 and ∼57%) and PD-1 (∼65 and ∼100%) synthesis, respectively, compared to NOD and NOD.Ifih1KO T cells following CVB3 infection. The Ifih1ΔHel1 mutation, but not the Ifih1KO mutation dampened IFN-α/β synthesis, reduced macrophage and T cell activation, and delayed both spontaneous and CVB3-accelerated T1D. Future studies will examine immune differences between NOD.Ifih1ΔHel1 and NOD.Ifih1KO mice that delay or promote autoimmunity, respectively.
S.I. Blum: None. Y. Chen: None. H.M. Tse: None.
American Diabetes Association (7-12-CD-11 to H.M.T.); National Institute of Diabetes and Digestive and Kidney Diseases (DK099550)