Endogenous retroviruses act as a tonic signal for Treg induction and oral tolerance development 3089

Abstract Description Endogenous retroviruses (ERVs) result from accumulated germline infections by ancient exogenous retroviruses and constitute a sizable proportion of the mammalian genome. Recent findings support the idea that these elements control tissue immune threshold of activation. In the skin, beneficial immunity to the microbiota depends on the ERV transcriptional activity of the host. How the crosstalk between ERVs and the microbiota controls tissue immunity at other barrier sites remains unknown. Our results reveal that antiretroviral (anti-RT) treatment (blocking the conversion of ERV into cDNA) impairs the induction of oral tolerance to food antigens. Further, ERV responses to food depend on the cGAS/STING pathway and type I IFN. Interestingly, blocking ERV expression during weaning also affects oral tolerance induction. Consistently, single-cell RNAseq data demonstrate that anti-RT treatment impacts regulatory T cell homeostasis and final differentiation within the gut, while also affecting mucosal dendritic cell functions in duodenum. We have also found that epithelial ERV expression is highly conserved across tissues and is not affected by the microbiota. Indeed, germ-free experiments suggest that ERV modulation of tolerance to food is independent of the microbiota. Altogether, our results propose that ERVs control gut immunoregulation by acting as a tonic signal required for Treg induction and differentiation thereby promoting oral tolerance and preventing allergic responses. Funding Sources This work was supported by the Division of Intramural Research of NIAID (NIAID; 1ZIA-AI001115 and 1ZIA-AI001132). C.A.R. is the Lorraine W. Egan Fellow of the Damon Runyon Cancer Research Foundation (grant DRG-2496-23). Topic Categories Mucosal and Regional Immunology (MUC)