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Proc Natl Acad Sci U S A. 2015 Oct 13;112(41):12770-5. doi: 10.1073/pnas.1516617112. Epub 2015 Sep 29.

Requirement of full TCR repertoire for regulatory T cells to maintain intestinal homeostasis.

Author information

1
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.
2
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;
3
Department of Immunology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-033, Japan;
4
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;
5
Department of Immunology, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan;
6
Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
7
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.

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.

KEYWORDS:

Helios; TCR repertoire; Treg; colitis; migratory DCs

PMID:
26420876
PMCID:
PMC4611614
DOI:
10.1073/pnas.1516617112
[Indexed for MEDLINE]
Free PMC Article

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