Cell Death and Type 1 Interferon Collaboratively Promote Virus-Induced Type I Immunity to Dietary Antigens

Celiac Disease (CD) is a lifelong immune-mediated enteropathy in which susceptible individuals develop an inflammatory T-helper-1 (Th1) immune response against dietary gluten leading to intestinal tissue damage and production of autoantibodies 1–3. Environmental factors have been proposed to play a role in the development of CD as only 1% of the genetically predisposed individuals develop the disease 2. Although epidemiological studies have highlighted a role of viral infections in the development of CD, mechanistic understanding by which viruses can trigger CD is unknown. Previous studies have shown that viruses from the same family that can induce protective immunity exhibit different immunopathology in the context of the immune response to food antigens. Specifically, acute infection with reovirus strains T1L and T3D-RV induced protective immunity but only T1L disrupted the immune response to dietary antigens as seen in CD 4. However, how T1L infection but not T3D-RV induced Th1 immunity against dietary antigens remains to be investigated. Here we show that differences between T1L and T3D-RV M1 and M2 genes determined the induction of Th1 immunity against dietary antigens. Furthermore, only T1L infection led to type I IFN signaling in dietary antigen-specific T cells in the mLNs and necroptosis in the epithelium. Through the expression of Clec9a, migratory cDC1s sensed necroptotic cells, which was necessary for the secretion of Th1-inducing cytokine IL-12, and uptook viral particles which drove induction of type I IFN. Collectively, our data demonstrated for the first time the coupling of cDC1-specific Clec9A sensing to Th1 immunity and established that several checkpoints are needed to drive Th1 immunity and prevent the tolerogenic response against dietary antigens. Overall, we propose that early events during viral infection could determine the ability of a virus to trigger immunopathology like CD later on in life.