Abstract
Retroelements are transposable elements that represent a significant portion of eukaryotic genomes. Here, we show that constitutive expression of endogenous retroelements play a key regulatory role in the acquisition of food tolerance. Specifically, inhibition of retroelement reverse transcription abolishes tolerance to dietary antigens and promotes allergic responses. This phenomenon is associated with impaired regulatory T cell differentiation/accumulation and altered dendritic cell tolerogenic function. Mechanistically, innate sensing of retroelement-derived cDNA via cGAS/STING within gut epithelial cells promotes a local tolerogenic milieu. Thus, within the gut, immune reactivity to retroelements act as a local tonic signal required for regulatory T cell induction and differentiation, thereby preventing allergic responses to food. Collectively, these findings uncover retroelements as key regulatory elements and essential allies in maintaining immune tolerance.