Transcription factor T-bet regulates intestinal inflammation mediated by innate lymphoid cells with the interleukin-7 receptor

Abstract Interactions between the innate immune system and the intestinal microbiota have an important role in the maintenance of mucosal homoeostasis. Indeed, impaired regulation of innate immune pathways are now considered to be a key driver of gut inflammation and may lead to the emergence of inflammatory bowel disease, such as ulcerative colitis or Crohn's disease. Mice lacking the transcription factor T-bet in the innate immune system develop microbiota-dependent colitis that resembles ulcerative colitis. Here, we show that inflammatory bowel disease in this model is mediated by a newly discovered population of innate immune cells termed innate lymphoid cells (ILCs) that selectively produce the inflammatory cytokine interleukin (IL) 17A. Depletion of intestinal ILCs, or blockade of the IL23/IL17 axis significantly attenuated chronic inflammatory bowel disease in these mice. We also show that elevated colonic production of tumour necrosis factor α (TNFα), a key cytokine involved in the pathogenesis of inflammatory bowel disease, was produced by CD103– CD11b+ intestinal dendritic cells (DCs). TNFα synergised with IL23 to drive IL-17A production by ILCs, demonstrating a previously unrecognised layer of cellular crosstalk between DCs and ILCs. Other cytokines implicated in pathogenesis of inflammatory bowel disease, such as TL1A and IL6, also promoted IL-17 production by ILCs, indicating that this novel intestinal innate immune cell population is responsive to other recognised inflammatory signals to drive gut inflammation. By sequencing bacterial rRNA genes we also identify a particular component of the intestinal microbiota of TRUC mice that drives excess TNF-α production and triggers colitis. Lastly, we show that T-bet is a transcriptional repressor of IL-7R expression, a key molecule involved in controlling intestinal ILC homoeostasis. The importance of IL-7R signalling 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 DCs, ILCs, and the intestinal microbiota. Funding Wellcome Trust.