MDA5 expression impacts immune cell activation during T1D development

Abstract Coxsackievirus B3 (CVB3) infection has been associated with triggering Type 1 diabetes (T1D), potentially due to direct β-cell damage and bystander activation of autoreactive T cells. CVB3-infection of Non-Obese Diabetic (NOD) mice accelerates T1D onset, in part due to melanoma differentiation-associated protein 5 (MDA5)-dependent antiviral responses. However, the role of MDA5 on immune cells during T1D remains unclear. By using mice that contain an in-frame deletion within the helicase 1 domain of MDA5 (ΔHel1) or lack MDA5 expression (KO), we can test the hypothesis that reduced MDA5 expression impairs IFN-α/β synthesis, immune cell activation, and T1D onset. NOD and KO mice develop T1D equally, but ΔHel1 mice exhibit delayed spontaneous and CVB3-accelerated T1D. During spontaneous T1D, 12-week-old ΔHel1 mice had a significant reduction in TNF+ F4/80+ macrophages (MΦ) (1.6-fold), perforin+ CD8+ T cells (13.1-fold), and IFNγ+ CD4+ T cells (6.1-fold), compared to NOD and KO mice. ΔHel1 mice had a significant reduction in pancreatic IFN-α (2.2-fold) and IFN-β (3.1-fold) levels compared to NOD mice following CVB3-infection. CVB3-infected ΔHel1 mice had a significant decrease in pancreatic TNF+ F4/80+ MΦ (2-fold) compared to NOD and KO mice. However, ΔHel1 and KO mice had reduced pancreatic perforin+ CD8+ T cells (2.5-fold) and IFNγ+ CD4+ T cells (1.8-fold) compared to NOD mice following CVB3 infection. The ΔHel1 mutation decreased basal and CVB3-responsive MΦ and T cells within the pancreata thereby delaying T1D onset. Yet, loss of MDA5 expression failed to delay T1D indicating MDA5-dependant responses may be required to prevent T1D. Future studies will determine if T1D onset is dictated by MDA5 dsRNA binding and/or ATPase activity.