title: Requirement of full TCR repertoire for regulatory T cells to maintain intestinal homeostasis.
abstract: The regulation of intestinal homeostasis by the immune system involves the dynamic interplay between gut commensal microbiota and resident immune cells. It is well known that a large and diverse lymphocyte antigen receptor repertoire enables the immune system to recognize and respond to a wide range of invading pathogens. There is also an emerging appreciation for a critical role the T-cell receptor (TCR) repertoire serves in the maintenance of peripheral tolerance by regulatory T cells (Tregs). Nevertheless, how the diversity of the TCR repertoire in Tregs affects intestinal homeostasis remains unknown. To address this question, we studied mice whose T cells express a restricted TCR repertoire. We observed the development of spontaneous colitis, accompanied by the induction of T-helper type 17 cells in the colon that is driven by gut commensal microbiota. We provide further evidence that a restricted TCR repertoire causes a loss of tolerogenicity to microbiota, accompanied by a paucity of peripherally derived, Helios(-) Tregs and hyperactivation of migratory dendritic cells. These results thus reveal a new facet of the TCR repertoire in which Tregs require a diverse TCR repitoire for intestinal homeostasis, suggesting an additional driving force in the evolutional significance of the TCR repertoire.
authors.affiliation: Department of Molecular Immunology, Institute of Industrial Science, The University of Tokyo, Meguro-ku, Tokyo 153-8505, Japan; Department of Immunology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-033, Japan; nishioj@iis.u-tokyo.ac.jp tada@m.u-tokyo.ac.jp.
authors.forename: Junko
authors.initials: J
authors.lastname: Nishio
authors.affiliation: Department of Molecular Immunology, Institute of Industrial Science, The University of Tokyo, Meguro-ku, Tokyo 153-8505, Japan; Department of Immunology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-033, Japan;
authors.forename: Minato
authors.initials: M
authors.lastname: Baba
authors.affiliation: Department of Immunology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-033, Japan;
authors.forename: Koji
authors.initials: K
authors.lastname: Atarashi
authors.affiliation: Department of Immunology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-033, Japan;
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tanoue
authors.affiliation: Department of Molecular Immunology, Institute of Industrial Science, The University of Tokyo, Meguro-ku, Tokyo 153-8505, Japan; Department of Immunology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-033, Japan;
authors.forename: Hideo
authors.initials: H
authors.lastname: Negishi
authors.affiliation: Department of Molecular Immunology, Institute of Industrial Science, The University of Tokyo, Meguro-ku, Tokyo 153-8505, Japan; Department of Immunology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-033, Japan; Max Planck-The University of Tokyo Center for Integrative Inflammology, Meguro-ku, Tokyo 153-8505, Japan;
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yanai
authors.affiliation: Department of Immunology, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan;
authors.forename: Sonoko
authors.initials: S
authors.lastname: Habu
authors.affiliation: Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Hori
authors.affiliation: Department of Immunology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-033, Japan;
authors.forename: Kenya
authors.initials: K
authors.lastname: Honda
authors.affiliation: Department of Molecular Immunology, Institute of Industrial Science, The University of Tokyo, Meguro-ku, Tokyo 153-8505, Japan; Department of Immunology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-033, Japan; Max Planck-The University of Tokyo Center for Integrative Inflammology, Meguro-ku, Tokyo 153-8505, Japan; nishioj@iis.u-tokyo.ac.jp tada@m.u-tokyo.ac.jp.
authors.forename: Tadatsugu
authors.initials: T
authors.lastname: Taniguchi
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D003106:Colon / Q000276:immunology* / Q000382:microbiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D064307:Microbiota / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology
chemical_list: D004268:DNA-Binding Proteins; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; C491746:Zfpn1a2 protein, mouse
keywords: Helios; TCR repertoire; Treg; colitis; migratory DCs