Loss of the microbiota unleashes harmful T cell responses against dietary antigen induced by enteric viruses

Introduction/Rationale: Celiac disease (CeD) is a complex disorder characterized by an inflammatory Th1-dominated CD4+ T cell response to gluten. CeD incidence has been rising in industrialized nations since the 1970s; it is not understood why, though studies have implicated viral infections and microbiome disruption in early life. In mice, specific enteric viruses have been shown to distort the response to dietary food antigen from a tolerizing pTreg-dominated to a Th1-dominated CD4+ response, perhaps the key priming event in CeD development. The microbiota can affect enteric viral replication and inflammatory potential, but how interplay between viruses and the microbiota shape dietary antigen responses is not understood. Given the frequency of broad-spectrum antibiotic administration to infants, there is strong potential for coincidence of enteric infections and microbiota disruptions during the critical period of gluten tolerization.

Methods: CD45.1+ OTII cells were transferred into mice either given antibiotics or maintained in GF conditions, then mice were gavaged with virus and exposed to new dietary antigen. OTII differentiation and cytokine production, as well as delayed-type hypersensitivity reactions, were examined in the treated mice.

Results: When the microbiota was removed, either in antibiotic-treated or germ-free mice, a normally innocuous reovirus became capable of driving strong Th1 polarization on dietary antigen reactive CD4+ T cells. Furthermore, the effects of enteric viruses harmful under normal conditions were also magnified by antibiotic treatment. This amplification was dependent on inflammatory cytokine production by a specific classical DC2 subset regulated by short-chain fatty acid GPCR signaling within the gut.

Conclusion: This suggests that the microbiota can protect against aberrant dietary antigen responses, and that early life antibiotic treatment may contribute to CeD initiation.