The transcription factor T-bet regulates intestinal inflammation mediated by interleukin-7 receptor+ innate lymphoid cells.
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.
Department of Experimental Immunobiology, Division of Transplantation Immunology and Mucosal Biology, King's College London, UK.
Nick
N
Powell
Alan W
AW
Walker
Emilie
E
Stolarczyk
James B
JB
Canavan
M Refik
MR
Gökmen
Ellen
E
Marks
Ian
I
Jackson
Ahmed
A
Hashim
Michael A
MA
Curtis
Richard G
RG
Jenner
Jane K
JK
Howard
Julian
J
Parkhill
Thomas T
TT
MacDonald
Graham M
GM
Lord
D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D003093:Colitis, Ulcerative / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000276:immunology*; D016998:Helicobacter / Q000276:immunology; D007113:Immunity, Innate; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020395:Receptors, Interleukin-7 / Q000276:immunology*; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000276:immunology*; D000098815:T-bet Transcription Factor
D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D020395:Receptors, Interleukin-7; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor