Journal
IMMUNITY
Volume 37, Issue 4, Pages 674-684Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2012.09.008
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Funding
- Medical Research Council [G0802068]
- Wellcome Trust [WT088747MA, WT076964]
- National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's
- St Thomas' National Health Service (NHS) Foundation Trust and King's College London
- Medical Research Council [MR/K002996/1, G0802068, G0600081, MR/J011118/1, MR/J006742/1] Funding Source: researchfish
- National Institute for Health Research [CL-2010-17-010, DRF-2009-02-22] Funding Source: researchfish
- National Institutes of Health Research (NIHR) [DRF-2009-02-22] Funding Source: National Institutes of Health Research (NIHR)
- MRC [MR/K002996/1, G0600081, MR/J011118/1, G0802068] Funding Source: UKRI
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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-7R alpha(+) innate lymphoid cells (ILCs) were potent promoters of disease in Tbx21(-/-)Rag2(-/-) ulcerative colitis (TRUC) mice. TNF-alpha 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-a alpha 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.
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