110-OR: MDA5-Dependent Responses Can Influence Spontaneous and Virus-Accelerated T1D Onset

Abstract

Coxsackievirus B3 (CVB3) infection promotes the activation of proinflammatory immune cells and is associated with triggering type 1 diabetes (T1D). We previously demonstrated that CVB3 infection of Non-Obese Diabetic (NOD) mice accelerates T1D, partly due to the activation of melanoma differentiation-associated protein 5 (MDA5)-dependent antiviral responses including IFN-α/β synthesis. Mutations within human IFIH1, the gene encoding MDA5, are correlated with T1D risk. Yet, the role of MDA5 on immune cells during T1D remains unknown. By utilizing mice that lack (KO) or contain an in-frame deletion within the helicase 1 domain of MDA5 (ΔHel1), we can test the hypothesis that reduced MDA5 responses delay T1D by decreasing IFN-α/β synthesis and immune cell activation. NOD and KO mice develop T1D similarly, but ΔHel1 mice have delayed spontaneous and CVB3-accelerated T1D. At 12 weeks of age during spontaneous T1D, ΔHel1 mice have a significant reduction in IFNγ+ CD4+ T cells (6.2-fold), perforin+ CD8+ T cells (13.2-fold), and TNF+ F4/80+ macrophages (MΦ) (1.7-fold) compared to NOD and KO mice. CVB3-infected ΔHel1 mice at day 3 exhibited a significant decrease in pancreatic IFN-α (2.2-fold) and IFN-β (3.1-fold) synthesis compared to NOD mice. At day 7 post-infection, ΔHel1 mice had a significant reduction in pancreatic TNF+ F4/80+ MΦ (2-fold) compared to NOD and KO mice. ΔHel1 and KO mice had reduced pancreatic IFNγ+ CD4+ T cells (1.9-fold) and perforin+ CD8+ T cells (2.6-fold) compared to NOD mice following CVB3 infection. This data demonstrated that the ΔHel1 mutation elicits a decrease in basal and CVB3-responsive MΦ and T cells within the pancreata to delay T1D. However, KO mice have impaired T cell responses to CVB3 and failed to delay spontaneous and CVB3-accelerated T1D indicating MDA5-dependent responses may be necessary for tolerance induction. Future studies will examine the mechanism of ΔHel1 T1D protection and whether MDA5 ATPase activity and/or dsRNA binding can modulate T1D development. Disclosure S. I. Blum: None. Y. Chen: None. H. M. Tse: None. Funding DK099550, DK127497, DK1264565, T32GM1097805, T32AI007051