CD8α+ cDC1s integrate cell death signals to initiate inflammatory T cell immunity to dietary antigens following reovirus infection

Abstract Most gastrointestinal viral infections are cleared without disrupting homeostatic responses and promoting immunopathology. However, there are also reports showing that viral infections promote loss of oral tolerance to dietary antigens and the development of celiac disease (CeD)1,2. We identified two strains of reovirus, T1L, and T3D-RV, that infect the gut and induce protective immunity, but differ in their capacity to induce pathogenic responses to dietary antigens as assessed by inhibition of peripheral regulatory T cell differentiation (pTregs) and induction of T-helper-1 (TH1) immunity1. Taking advantage of this infection model, we sought to define the mechanisms through which reovirus T1L infection blocks pTreg differentiation and induces TH1 cells to dietary antigens. At homeostasis, migratory conventional type 1 dendritic cells (cDC1) are the key DC subset instructing tolerogenic responses to dietary antigens. Here, we report that following T1L infection, the migratory CD8α+ cDC1 subset is central to the development of TH1 immunity to dietary antigens upon sensing necroptotic epithelial cells via the C-type lectin domain family 9 member (Clec9a). Furthermore, we identified the viral determinants required for the induction of TH1 and discovered that the development of TH1 immunity to dietary antigens is more tightly controlled than the loss of differentiation of pTregs. More specifically, while type-I interferon signaling was sufficient to block differentiation of pTregs, IL-12 production induced upon sensing of necroptotic cells was additionally required for initiation of TH1 immunity. Overall, our work demonstrates a non-redundant role for necroptosis and the migratory CD8α+ cDC1 subset in initiating inflammatory responses to normally innocuous dietary antigens in the context of viral infection.