Th17-cell plasticity in Helicobacter hepaticus-induced intestinal inflammation

Mucosal Immunol. 2013 Nov;6(6):1143-56. doi: 10.1038/mi.2013.11. Epub 2013 Mar 6.

Abstract

Bacterial-induced intestinal inflammation is crucially dependent on interleukin (IL)-23 and is associated with CD4(+) T helper type 1 (Th1) and Th17 responses. However, the relative contributions of these subsets during the induction and resolution of colitis in T-cell-sufficient hosts remain unknown. We report that Helicobacter hepaticus-induced typhlocolitis in specific pathogen-free IL-10(-/-) mice is associated with elevated frequencies and numbers of large intestinal interferon (IFN)-γ(+) and IFN-γ(+)IL-17A(+) CD4(+) T cells. By assessing histone modifications and transcript levels in IFN-γ(+), IFN-γ(+)IL-17A(+), and IL-17A(+) CD4(+) T cells isolated from the inflamed intestine, we show that Th17 cells are predisposed to upregulate the Th1 program and that they express IL-23R but not IL-12R. Using IL-17A fate-reporter mice, we further demonstrate that H. hepaticus infection gives rise to Th17 cells that extinguish IL-17A secretion and turn on IFN-γ within 10 days post bacterial inoculation. Together, our results suggest that bacterial-induced Th17 cells arising in disease-susceptible hosts contribute to intestinal pathology by switching phenotype, transitioning via an IFN-γ(+)IL-17A(+) stage, to become IFN-γ(+) ex-Th17 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Colitis / etiology
  • Colitis / immunology*
  • Helicobacter Infections / complications
  • Helicobacter Infections / immunology*
  • Helicobacter hepaticus / immunology*
  • Humans
  • Inflammation / microbiology
  • Interferon-gamma / metabolism
  • Interleukin-10 / genetics
  • Interleukin-10 / metabolism
  • Interleukin-17 / metabolism
  • Interleukin-23 / metabolism
  • Intestines / immunology*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Organ Culture Techniques
  • Th1 Cells / immunology*
  • Th17 Cells / immunology*
  • Typhlitis / etiology
  • Typhlitis / immunology*

Substances

  • Interleukin-17
  • Interleukin-23
  • Interleukin-10
  • Interferon-gamma