By using high-throughput sequencing of T-cell receptors, this study shows that thymus-derived regulatory T (Treg) cells constitute most Treg cells in all lymphoid and intestinal organs, including the colon, suggesting that thymic Treg cells and not induced Treg cells dominantly control tolerance to the gut’s antigens such as commensal microbiota. The identity of the intestinal regulatory T (Treg) cells that control autoimmune diseases such as colitis and immune responses to commensal microbes remains ill defined. In this study Anna Cebula et al. use high-throughput sequencing of T-cell receptors to show that the predominant Treg cells in all lymphoid and intestinal organs, including the colon, are derived from the thymus. This challenges the view that induced rather than thymic Treg cells are mainly responsible for the control of intestinal inflammation, although it does not exclude the possibility that induced Treg cells contribute to intestinal homeostasis. Peripheral mechanisms preventing autoimmunity and maintaining tolerance to commensal microbiota involve CD4+Foxp3+ regulatory T (Treg) cells1,2 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 Treg cells and induced Treg cells are biased towards self and non-self antigens, respectively3,4,5,6, but their relative contribution in controlling immunopathology, such as colitis and other untoward inflammatory responses triggered by different types of antigens, remains unresolved7. 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 Treg cells and other T-cell populations are exposed. Intestinal environments can enhance conversion to a regulatory lineage8,9 and favour tolerogenic presentation of antigens to naive CD4+ T cells10,11, suggesting that intestinal homeostasis depends on microbiota-specific induced Treg cells12,13,14,15. Here, to identify the origin and antigen-specificity of intestinal Treg 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 Treg cells constitute most Treg 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 Treg cells, and not induced Treg cells, dominantly mediate tolerance to antigens produced by intestinal commensals.

For more than 50 years, investigators have unsuccessfully tried to recreate in experimental animals the cardiovascular complications of diabetes seen in humans. In particular, accelerated atherosclerosis and dilated cardiomyopathy, the major causes of mortality in patients with diabetes, have been conspicuously absent in many mouse models of the disease. Under the auspices of the NIH, the Animal Models of Diabetic Complications Consortium has worked to address this issue. This effort has focused on the development of mouse models because of the high level of genomic information available and the many well-developed genetic manipulations that may be performed in mice. Importantly, the consortium has also worked to standardize many methods to assess metabolic and cardiovascular end points for measurement of the diabetic state and its macrovascular complications. Finally, for maximum benefits from these animal models in the study of atherosclerosis and of other diabetic complications, the consortium has created a system for sharing both the animal models and the accumulated phenotypic data with the greater scientific community.