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

N Powell, AW Walker, E Stolarczyk, JB Canavan… - Immunity, 2012 - cell.com
N Powell, AW Walker, E Stolarczyk, JB Canavan, MR Gökmen, E Marks, I Jackson…
Immunity, 2012cell.com
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 …
Summary
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 CD103CD11b+ 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.
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