title: Regulatory T cells suppress development of colitis, blocking differentiation of T-helper 17 into alternative T-helper 1 cells.
abstract: OBJECTIVE
  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 naïve 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 naïve 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-17A⁻IFN-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.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Sujino
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ono
authors.forename: Yohei
authors.initials: Y
authors.lastname: Mikami
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hayashi
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Doi
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Matsuoka
authors.forename: Tadakazu
authors.initials: T
authors.lastname: Hisamatsu
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Takaishi
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Ogata
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Dan R
authors.initials: DR
authors.lastname: Littman
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hibi
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D003092:Colitis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D018417:Th1 Cells / Q000166:cytology* / Q000502:physiology; D058504:Th17 Cells / Q000166:cytology* / Q000502:physiology
chemical_list: D015704:CD4 Antigens; D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D007371:Interferon-gamma