The transcription factor T-bet regulates intestinal inflammation mediated by interleukin-7 receptor+ innate lymphoid cells

Nick Powell, Alan W Walker, Emilie Stolarczyk, James B Canavan, M Refik Gökmen, Ellen Marks, Ian Jackson, Ahmed Hashim, Michael A Curtis, Richard G Jenner, Jane K Howard, Julian Parkhill, Thomas T MacDonald, Graham M Lord

Research output: Contribution to journalArticlepeer-review

222 Citations (Scopus)

Abstract

Mice lacking the transcription factor T-bet in the innate immune system develop microbiota-dependent colitis. Here, we show that interleukin-17A (IL-17A)-producing IL-7Rα(+) innate lymphoid cells (ILCs) were potent promoters of disease in Tbx21(-/-)Rag2(-/-) ulcerative colitis (TRUC) mice. TNF-α produced by CD103(-)CD11b(+) dendritic cells synergized with IL-23 to drive IL-17A production by ILCs, demonstrating a previously unrecognized layer of cellular crosstalk between dendritic cells and ILCs. We have identified Helicobacter typhlonius as a key disease trigger driving excess TNF-α production and promoting colitis in TRUC mice. Crucially, T-bet also suppressed the expression of IL-7R, a key molecule involved in controlling intestinal ILC homeostasis. The importance of IL-7R signaling in TRUC disease was highlighted by the dramatic reduction in intestinal ILCs and attenuated colitis following IL-7R blockade. Taken together, these data demonstrate the mechanism by which T-bet regulates the complex interplay between mucosal dendritic cells, ILCs, and the intestinal microbiota.
Original languageEnglish
Pages (from-to)674-684
Number of pages11
JournalImmunity
Volume37
Issue number4
DOIs
Publication statusPublished - 19 Oct 2012

Keywords

  • animals
  • cells, cultured
  • chronic disease
  • colitis, ulcerative
  • DNA-binding proteins
  • helicobacter
  • immunity, innate
  • lymphocytes
  • mice
  • mice, inbred BALB C
  • mice, knockout
  • receptors, interleukin-7
  • signal transduction
  • t-box domain proteins

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