title: Peripheral education of the immune system by colonic commensal microbiota.
abstract: The instruction of the immune system to be tolerant of self, thereby preventing autoimmunity, is facilitated by the education of T cells in a specialized organ, the thymus, in which self-reactive cells are either eliminated or differentiated into tolerogenic Foxp3(+) regulatory T (T(reg)) cells. However, it is unknown whether T cells are also educated to be tolerant of foreign antigens, such as those from commensal bacteria, to prevent immunopathology such as inflammatory bowel disease. Here we show that encounter with commensal microbiota results in the peripheral generation of T(reg) cells rather than pathogenic effectors. We observed that colonic T(reg) cells used T-cell antigen receptors (TCRs) different from those used by T(reg) cells in other locations, implying an important role for local antigens in shaping the colonic T(reg)-cell population. Many of the local antigens seemed to be derived from commensal bacteria, on the basis of the in vitro reactivity of common colon T(reg) TCRs. These TCRs did not facilitate thymic T(reg)-cell development, implying that many colonic T(reg) cells arise instead by means of antigen-driven peripheral T(reg)-cell development. Further analysis of two of these TCRs by the creation of retroviral bone marrow chimaeras and a TCR transgenic line revealed that microbiota indigenous to our mouse colony was required for the generation of colonic T(reg) cells from otherwise naive T cells. If T cells expressing these TCRs fail to undergo T(reg)-cell development and instead become effector cells, they have the potential to induce colitis, as evidenced by adoptive transfer studies. These results suggest that the efficient peripheral generation of antigen-specific populations of T(reg) cells in response to an individual's microbiota provides important post-thymic education of the immune system to foreign antigens, thereby providing tolerance to commensal microbiota.
authors.affiliation: Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Lathrop
authors.forename: Seth M
authors.initials: SM
authors.lastname: Bloom
authors.forename: Sindhuja M
authors.initials: SM
authors.lastname: Rao
authors.forename: Katherine
authors.initials: K
authors.lastname: Nutsch
authors.forename: Chan-Wang
authors.initials: CW
authors.lastname: Lio
authors.forename: Nicole
authors.initials: N
authors.lastname: Santacruz
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Peterson
authors.forename: Thaddeus S
authors.initials: TS
authors.lastname: Stappenbeck
authors.forename: Chyi-Song
authors.initials: CS
authors.lastname: Hsieh
mesh_terms: D000818:Animals; D003092:Colitis / Q000276:immunology / Q000517:prevention & control; D003106:Colon / Q000166:cytology / Q000276:immunology* / Q000382:microbiology*; D007107:Immune System / Q000166:cytology / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology; D018928:Immunity, Mucosal / Q000276:immunology; D054892:Metagenome / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
chemical_list: D011948:Receptors, Antigen, T-Cell