RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F

Gastroenterology. 2009 Jan;136(1):257-67. doi: 10.1053/j.gastro.2008.10.018. Epub 2008 Oct 9.

Abstract

Background and aims: IL-17-producing CD4(+) T-helper cells (Th17) contribute to chronic autoimmune inflammation in the brain, and levels of Th17-derived cytokines increase in patients with colitis, suggesting a role in pathogenesis. We analyzed the roles of Th17 cells and the transcription factor retinoic acid receptor-related organ receptor (ROR)gamma, which regulates Th17 differentiation, in chronic intestinal inflammation.

Methods: Using an adoptive transfer model of colitis, we compared the colitogenic potential of wild-type, interleukin-17A (IL-17A)-, IL-17F-, IL-22-, and RORgamma-deficient CD4(+)CD25(-) T cells in RAG1-null mice.

Results: Adoptive transfer of IL-17A-, IL-17F-, or IL-22-deficient T lymphocytes into RAG1-null mice caused severe colitis that was indistinguishable from that caused by wild-type cells. In contrast, transfer of RORgamma-null T cells failed to increase mucosal IL-17 cytokine levels and did not induce colitis. Treatment with IL-17A was able to restore colitis after transfer of RORgamma-null T cells, indicating a crucial role for Th17 cells in pathogenesis. Treatment of RAG1 mice that received IL-17F-null (but not wild-type) T cells with a neutralizing anti-IL-17A antibody significantly suppressed disease, indicating redundant biological effects of IL-17A and IL-17F.

Conclusions: We have identified a crucial role of RORgamma-expressing Th17 cells in chronic intestinal inflammation. RORgamma controls IL-17A and IL-17F production, and these cytokines have a redundant but highly pathogenic role in gut inflammation. Reagents that target RORgamma or a combination of anti-IL-17A and anti-IL-17F might be developed as therapeutics for chronic colitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Cell Movement
  • Cells, Cultured
  • Chronic Disease
  • Colitis / etiology*
  • Cytokines / biosynthesis
  • Dendritic Cells / physiology
  • Interleukin-17 / physiology*
  • Interleukins / physiology
  • Mice
  • Mice, Inbred C57BL
  • Neutrophils / physiology
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Receptors, Retinoic Acid / analysis
  • Receptors, Retinoic Acid / physiology*
  • Receptors, Thyroid Hormone / analysis
  • Receptors, Thyroid Hormone / physiology*
  • T-Lymphocytes, Helper-Inducer / physiology*

Substances

  • Cytokines
  • Interleukin-17
  • Interleukins
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Receptors, Retinoic Acid
  • Receptors, Thyroid Hormone
  • Rorc protein, mouse
  • interleukin-22