Commensal bacteria promote type I interferon signaling to maintain immune tolerance

ABSTRACT Type I interferons (IFN) exert a broad range of biological effects important in coordinating immune responses. Host and microbial factors regulate IFN production, triggering a signaling cascade that has classically been studied in the context of pathogen clearance. In particular, commensal bacteria have been shown to induce IFN to protect against viral infections. Yet, whether immunomodulatory bacteria operate through IFN pathways to support immune tolerance remains elusive. Here, we demonstrate microbiota-dependent IFN signaling is required for priming tolerogenic T regulatory cells (Tregs) by intestinal dendritic cells (DCs). DCs deficient in IFN signaling through deletion of IFNAR-1 display dysregulated cytokine production in response to the commensal bacteria Bacteroides fragilis , resulting in blunted downstream Treg responses. Single cell RNA sequencing of gut tissues demonstrated that colonization with B. fragilis promotes a distinct type I IFN gene signature in Tregs during homeostasis and intestinal inflammation. Moreover, B. fragilis- mediated protection during experimental colitis was abrogated in IFNAR1-deficient mice. Altogether, our findings demonstrate an important role of microbiota-mediated immune tolerance via tonic type I IFN signaling.