Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells

Research output: Contribution to journalArticle

Authors

  • Matthew R. Hepworth
  • Xinxin Wang
  • Emma C. Mackley
  • Emily E. Halford
  • Emma E. Dutton
  • Clare L. Marriott
  • Verena Brucklacher-Waldert
  • Marc Veldhoen
  • Judith Kelsen
  • Robert N. Baldassano
  • Gregory F. Sonnenberg

Colleges, School and Institutes

Abstract

RAR-related orphan receptor-γt (ROR-γt) directs differentiation of proinflammatory T helper 17 (TH17) cells and is a potential therapeutic target in chronic autoimmune and inflammatory diseases. However, ROR-γt-dependent group 3 innate lymphoid cells ILC3s provide essential immunity and tissue protection in the intestine, suggesting that targeting ROR-γt could also result in impaired host defense after infection or enhanced tissue damage. Here, we demonstrate that transient chemical inhibition of ROR-γt in mice selectively reduces cytokine production from TH17 but not ILCs in the context of intestinal infection with Citrobacter rodentium, resulting in preserved innate immunity. Temporal deletion of Rorc (encoding ROR-γt) in mature ILCs also did not impair cytokine response in the steady state or during infection. Finally, pharmacologic inhibition of ROR-γt provided therapeutic benefit in mouse models of intestinal inflammation and reduced the frequency of TH17 cells but not ILCs isolated from primary intestinal samples of individuals with inflammatory bowel disease (IBD). Collectively, these results reveal differential requirements for ROR-γt in the maintenance of TH17 cell and ILC3 responses and suggest that transient inhibition of ROR-γt is a safe and effective therapeutic approach during intestinal inflammation.

Details

Original languageEnglish
Pages (from-to)319-323
Number of pages5
JournalNature Medicine
Volume22
Issue number3
Early online date15 Feb 2016
Publication statusPublished - Mar 2016

Keywords

  • Chronic inflammation, Innate lymphoid cells, Translational research