The Transcription Factor T-bet Regulates Intestinal Inflammation Mediated by Interleukin-7 Receptor(+) Innate Lymphoid Cells

TY - JOUR

T1 - The Transcription Factor T-bet Regulates Intestinal Inflammation Mediated by Interleukin-7 Receptor(+) Innate Lymphoid Cells

AU - Powell, Nicholas

AU - Walker, Alan W.

AU - Stolarczyk, Emilie

AU - Canavan, James B.

AU - Goekmen, M. Refik

AU - Marks, Ellen

AU - Jackson, Ian

AU - Hashim, Ahmed

AU - Curtis, Michael A.

AU - Jenner, Richard G.

AU - Howard, Jane K.

AU - Parkhill, Julian

AU - MacDonald, Thomas T.

AU - Lord, Graham M.

PY - 2012/10/19

Y1 - 2012/10/19

N2 - 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.

AB - 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.

U2 - 10.1016/j.immuni.2012.09.008

DO - 10.1016/j.immuni.2012.09.008

M3 - Article

SN - 1074-7613

VL - 37

SP - 674

EP - 684

JO - Immunity

JF - Immunity

IS - 4

ER -