TY - JOUR
T1 - Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota
AU - Cebula, Anna
AU - Seweryn, Michal
AU - Rempala, Grzegorz A.
AU - Pabla, Simarjot Singh
AU - McIndoe, Richard A
AU - Denning, Timothy L.
AU - Bry, Lynn
AU - Kraj, Piotr
AU - Kisielow, Pawel
AU - Ignatowicz, Leszek
N1 - Funding Information:
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.Liuinthe HDDCMicrobiome Core,withadditionalreviewoffindings 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.
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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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U2 - 10.1038/nature12079
DO - 10.1038/nature12079
M3 - Article
C2 - 23624374
AN - SCOPUS:84877742439
SN - 0028-0836
VL - 497
SP - 258
EP - 262
JO - Nature
JF - Nature
IS - 7448
ER -