Regulatory T cells suppress development of colitis, blocking differentiation of T-helper 17 into alternative T-helper 1 cells

Tomohisa Sujino, Takanori Kanai, Yuichi Ono, Yohei Mikami, Atsushi Hayashi, Tomomitsu Doi, Katsuyoshi Matsuoka, Tadakazu Hisamatsu, Hiromasa Takaishi, Haruhiko Ogata, Akihiko Yoshimura, Dan R. Littman, Toshifumi Hibi

Research output: Contribution to journalArticlepeer-review

47 Citations (Scopus)

Abstract

Background & Aims: Although T-helper (Th) 17 and Th1 cells are involved in pathogenesis of intestinal inflammation, their developmental pathways and sufficiency to promote disease are not known; nor are the roles of CD4 +CD25+ regulatory T (TR) cells in their development. Methods: We performed adoptive transfer experiments to investigate the induction and suppression of colitis using nave CD4+CD45RB high T cells and/or CD4+CD25+ TR cells that were obtained from retinoid-related orphan receptor gamma t (RORγt) gfp/+ or Ly5.1/Ly5.2 congenic mice. Results: We observed 3 types of colitogenic CD4+ Th1 cells (interleukin [IL]-17A-interferon [IFN]-γ+): RORγt classical Th1 cells that differentiated directly from nave T cells; RORγt + Th1-like cells; and RORγt alternative Th1 cells that were terminally differentiated from RORγt+ cells via Th17 (IL-17A+IFN-γ), Th17/Th1 (IL-17A+IFN- γ+), or Th1-like (IL-17AIFN-γ+) cells. In this pathway, CD4+CD25+ TR cells suppress the development of not only classical Th1 cells, but also alternative Th1 cells at the transition of Th17/Th1 into alternative Th1 cells, resulting in accumulation of Th17 and Th17/Th1 cells in mice in which the development of colitis was suppressed. Furthermore, TR cells regulated the established balance of Th17 and Th1 cells under colitic conditions to yield a high ratio of Th17 and Th17/Th1 cells to Th1 cells in noncolitic conditions. Conclusions: Th17 and Th17/Th1 cells become colitogenic alternative Th1 cells via Th17, Th17/Th1, and Th1-like cells, independently of classical Th1 cells. TR cells suppress this pathway, resulting in accumulation of Th17 and Th17/Th1 cells.

Original languageEnglish
Pages (from-to)1014-1023
Number of pages10
JournalGastroenterology
Volume141
Issue number3
DOIs
Publication statusPublished - 2011 Sep

Keywords

  • Immune Response
  • Inflammatory Bowel Disease
  • Mouse Model
  • T-Cell Development

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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