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

Gastroenterology. 2011 Sep;141(3):1014-23. doi: 10.1053/j.gastro.2011.05.052. Epub 2011 Jun 7.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4 Antigens / metabolism
  • Cell Differentiation / physiology*
  • Colitis / metabolism
  • Colitis / pathology*
  • Colitis / physiopathology*
  • Disease Models, Animal
  • Interferon-gamma / metabolism
  • Interleukin-17 / metabolism
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Intestinal Mucosa / metabolism
  • Mice
  • Mice, Congenic
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • T-Lymphocytes, Regulatory / physiology*
  • Th1 Cells / cytology*
  • Th1 Cells / physiology
  • Th17 Cells / cytology*
  • Th17 Cells / physiology

Substances

  • CD4 Antigens
  • Interleukin-17
  • Interleukin-2 Receptor alpha Subunit
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Interferon-gamma