Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 41, Pages 12770-12775Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1516617112
Keywords
TCR repertoire; colitis; Treg; Helios; migratory DCs
Categories
Funding
- CREST of the Japan Science and Technology Agency
- Ministry of Education, Culture, Sports, and Science
- Life Science Foundation of Japan
- Research Foundation for Pharmaceutical Sciences
- Mishima Kaiun Memorial Foundation
- Yakult-Bioscience Foundation
- Naito Foundation
- BONAC Corporation
- Kyowa Hakko Kirin Co., Ltd.
- Grants-in-Aid for Scientific Research [14F04416, 15H05787, 15H04747] Funding Source: KAKEN
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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.
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