Abstract
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.
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Acknowledgements
This work was supported by basic research grants from the National Institutes of Health (NIH; AI 5R01AI079277 to L.I., and DMS1106485 and R01CA152158 to G.A.R.). The Harvard Digestive Disease Center (HDDC) Microbiome Core facility is supported by P30-DK034854 and Brigham and Women’s Hospital in Boston, Massachusetts. Microbiological analyses were performed by M. Delaney, A. Dubois and Q. Liu in the HDDC Microbiome Core, with additional review of findings by A. B. Onderdonk. We thank J. Pihkala and H. Ignatowicz for technical assistance, M. Kuczma, L. Wojciech, E. Szurek, A. Miazek and P. Muranski for discussion and R. Markowitz for editing the manuscript.
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A.C. performed most experiments and analysed the data; M.S. and G.A.R. performed statistical analyses; S.S.P. and R.A.M. designed the PACE program; T.L.D. provided expertise in colonic T-cell isolation; L.B. performed the microbiological study; P.Kr. established TCRmini and Foxp3GFP mice models; P.Ki. and L.I. designed the study, analysed the data and wrote the paper.
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Cebula, A., Seweryn, M., Rempala, G. et al. Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. Nature 497, 258–262 (2013). https://doi.org/10.1038/nature12079
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DOI: https://doi.org/10.1038/nature12079
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