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

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213 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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  • Cite this

    Powell, N., Walker, A. W., Stolarczyk, E., Canavan, J. B., Gökmen, M. R., Marks, E., Jackson, I., Hashim, A., Curtis, M. A., Jenner, R. G., Howard, J. K., Parkhill, J., MacDonald, T. T., & Lord, G. M. (2012). The transcription factor T-bet regulates intestinal inflammation mediated by interleukin-7 receptor+ innate lymphoid cells. Immunity, 37(4), 674-684. https://doi.org/10.1016/j.immuni.2012.09.008