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 journalArticle

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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 (T R) 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 + T R 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 + T R 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, T R 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. T R 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

Fingerprint

Th1 Cells
Regulatory T-Lymphocytes
Colitis
Th17 Cells
Interleukin-17
Interferons
Congenic Mice
T-Lymphocytes
Adoptive Transfer

Keywords

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

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Regulatory T cells suppress development of colitis, blocking differentiation of T-helper 17 into alternative T-helper 1 cells. / Sujino, Tomohisa; Kanai, Takanori; Ono, Yuichi; Mikami, Yohei; Hayashi, Atsushi; Doi, Tomomitsu; Matsuoka, Katsuyoshi; Hisamatsu, Tadakazu; Takaishi, Hiromasa; Ogata, Haruhiko; Yoshimura, Akihiko; Littman, Dan R.; Hibi, Toshifumi.

In: Gastroenterology, Vol. 141, No. 3, 09.2011, p. 1014-1023.

Research output: Contribution to journalArticle

Sujino, Tomohisa ; Kanai, Takanori ; Ono, Yuichi ; Mikami, Yohei ; Hayashi, Atsushi ; Doi, Tomomitsu ; Matsuoka, Katsuyoshi ; Hisamatsu, Tadakazu ; Takaishi, Hiromasa ; Ogata, Haruhiko ; Yoshimura, Akihiko ; Littman, Dan R. ; Hibi, Toshifumi. / Regulatory T cells suppress development of colitis, blocking differentiation of T-helper 17 into alternative T-helper 1 cells. In: Gastroenterology. 2011 ; Vol. 141, No. 3. pp. 1014-1023.
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AU - Sujino, Tomohisa

AU - Kanai, Takanori

AU - Ono, Yuichi

AU - Mikami, Yohei

AU - Hayashi, Atsushi

AU - Doi, Tomomitsu

AU - Matsuoka, Katsuyoshi

AU - Hisamatsu, Tadakazu

AU - Takaishi, Hiromasa

AU - Ogata, Haruhiko

AU - Yoshimura, Akihiko

AU - Littman, Dan R.

AU - Hibi, Toshifumi

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N2 - 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 (T R) 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 + T R 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 + T R 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, T R 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. T R cells suppress this pathway, resulting in accumulation of Th17 and Th17/Th1 cells.

AB - 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 (T R) 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 + T R 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 + T R 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, T R 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. T R cells suppress this pathway, resulting in accumulation of Th17 and Th17/Th1 cells.

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