title: RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F.
abstract: OBJECTIVE
  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.
authors.affiliation: Institute of Molecular Medicine, University of Mainz, Mainz, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Leppkes
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker
authors.forename: Ivaylo I
authors.initials: II
authors.lastname: Ivanov
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hirth
authors.forename: Stefan
authors.initials: S
authors.lastname: Wirtz
authors.forename: Clemens
authors.initials: C
authors.lastname: Neufert
authors.forename: Sandrine
authors.initials: S
authors.lastname: Pouly
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.forename: David M
authors.initials: DM
authors.lastname: Valenzuela
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.forename: Burkhard
authors.initials: B
authors.lastname: Becher
authors.forename: Dan R
authors.initials: DR
authors.lastname: Littman
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D002908:Chronic Disease; D003092:Colitis / Q000209:etiology*; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000502:physiology; D020381:Interleukin-17 / Q000502:physiology*; D007378:Interleukins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000502:physiology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018168:Receptors, Retinoic Acid / Q000032:analysis / Q000502:physiology*; D011988:Receptors, Thyroid Hormone / Q000032:analysis / Q000502:physiology*; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology*; D000097043:Interleukin-22
chemical_list: D016207:Cytokines; D020381:Interleukin-17; D007378:Interleukins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D000097043:Interleukin-22; C539901:Rorc protein, mouse