Peripheral mechanisms preventing autoimmunity and maintaining tolerance to commensal microbiota involve CD4 + Foxp3 + regulatory T (T reg) cells generated in the thymus or extrathymically by induction of naive CD4 + Foxp3-T cells. Previous studies suggested that the T-cell receptor repertoires of thymic T reg cells and induced T reg cells are biased towards self and non-self antigens, respectively, but their relative contribution in controlling immunopathology, such as colitis and other untoward inflammatory responses triggered by different types of antigens, remains unresolved. The intestine, and especially the colon, is a particularly suitable organ to study this question, given the variety of self-, microbiota-and food-derived antigens to which T reg cells and other T-cell populations are exposed. Intestinal environments can enhance conversion to a regulatory lineage and favour tolerogenic presentation of antigens to naive CD4 + T cells, suggesting that intestinal homeostasis depends on microbiota-specific induced T reg cells. Here, to identify the origin and antigen-specificity of intestinal T reg cells, we performed single-cell and high-throughput sequencing of the T-cell receptor repertoires of CD4 + Foxp3 + and CD4 + Foxp3-T cells, and analysed their reactivity against specific commensal species. We show that thymus-derived T reg cells constitute most T reg cells in all lymphoid and intestinal organs, including the colon, where their repertoire is heavily influenced by the composition of the microbiota. Our results suggest that thymic T reg cells, and not induced T reg cells, dominantly mediate tolerance to antigens produced by intestinal commensals.
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