title: Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota.
abstract: Peripheral mechanisms preventing autoimmunity and maintaining tolerance to commensal microbiota involve CD4(+) Foxp3(+) regulatory T (Treg) 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 Treg cells and induced Treg 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 Treg 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 Treg cells. 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.
authors.affiliation: Center for Biotechnology and Genomic Medicine, Georgia Regents University, Augusta, Gerogia 30912, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Cebula
authors.forename: Michal
authors.initials: M
authors.lastname: Seweryn
authors.forename: Grzegorz A
authors.initials: GA
authors.lastname: Rempala
authors.forename: Simarjot Singh
authors.initials: SS
authors.lastname: Pabla
authors.forename: Richard A
authors.initials: RA
authors.lastname: McIndoe
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Denning
authors.forename: Lynn
authors.initials: L
authors.lastname: Bry
authors.forename: Piotr
authors.initials: P
authors.lastname: Kraj
authors.forename: Pawel
authors.initials: P
authors.lastname: Kisielow
authors.forename: Leszek
authors.initials: L
authors.lastname: Ignatowicz
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000942:Antigens, Bacterial / Q000276:immunology; D003106:Colon / Q000187:drug effects / Q000276:immunology / Q000382:microbiology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing; D006706:Homeostasis / Q000187:drug effects / Q000276:immunology; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D059010:Single-Cell Analysis; D013559:Symbiosis / Q000187:drug effects / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D060168:Thymocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*
chemical_list: D000900:Anti-Bacterial Agents; D000942:Antigens, Bacterial; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011948:Receptors, Antigen, T-Cell