Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota

Anna Cebula, Michal Seweryn, Grzegorz A. Rempala, Simarjot Singh Pabla, Richard A McIndoe, Timothy L. Denning, Lynn Bry, Piotr Kraj, Pawel Kisielow, Leszek Ignatowicz

Research output: Contribution to journalArticle

185 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)258-262
Number of pages5
JournalNature
Volume497
Issue number7448
DOIs
StatePublished - Apr 29 2013

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Microbiota
Regulatory T-Lymphocytes
Thymus Gland
Antigens
T-Lymphocytes
T-Cell Antigen Receptor
Colon
Antigen Presentation
Colitis
Autoimmunity
Intestines
Homeostasis
Food

ASJC Scopus subject areas

  • General

Cite this

Cebula, A., Seweryn, M., Rempala, G. A., Pabla, S. S., McIndoe, R. A., Denning, T. L., ... Ignatowicz, L. (2013). Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. Nature, 497(7448), 258-262. https://doi.org/10.1038/nature12079

Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. / Cebula, Anna; Seweryn, Michal; Rempala, Grzegorz A.; Pabla, Simarjot Singh; McIndoe, Richard A; Denning, Timothy L.; Bry, Lynn; Kraj, Piotr; Kisielow, Pawel; Ignatowicz, Leszek.

In: Nature, Vol. 497, No. 7448, 29.04.2013, p. 258-262.

Research output: Contribution to journalArticle

Cebula, A, Seweryn, M, Rempala, GA, Pabla, SS, McIndoe, RA, Denning, TL, Bry, L, Kraj, P, Kisielow, P & Ignatowicz, L 2013, 'Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota', Nature, vol. 497, no. 7448, pp. 258-262. https://doi.org/10.1038/nature12079
Cebula A, Seweryn M, Rempala GA, Pabla SS, McIndoe RA, Denning TL et al. Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. Nature. 2013 Apr 29;497(7448):258-262. https://doi.org/10.1038/nature12079
Cebula, Anna ; Seweryn, Michal ; Rempala, Grzegorz A. ; Pabla, Simarjot Singh ; McIndoe, Richard A ; Denning, Timothy L. ; Bry, Lynn ; Kraj, Piotr ; Kisielow, Pawel ; Ignatowicz, Leszek. / Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. In: Nature. 2013 ; Vol. 497, No. 7448. pp. 258-262.
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