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

Abstract

SummaryMice 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.

Developing in vitro expanded CD45RA+regulatory T cells as an adoptive cell therapy for Crohn's disease

“…LP mononuclear cells (LPMCs) and MLN mononuclear cells (MLNMCs) were isolated as described previously52 and listed in online supplemental methods.…”

Recent advances in inflammatory bowel disease: mucosal immune cells in intestinal inflammation

“…Group 1 ILCs produce IFNγ and comprise NK cells and ILC1; group 2 produce Th2 cytokines such as IL-5 and IL-13 and are dependent on transcription factors GATA-binding protein-3 (GATA3) and retinoic acid receptor-related orphan receptor-α (RORα); and group 3 includes all ILC subtypes that produce IL-17 and/or IL-22 and depend on the transcription factor RORγt for their development and function 95. These three subsets broadly parallel the major T helper cell subsets with regard to their signature cytokines (eg, group 1 ILCs, Th1; group 2 ILCs, Th2; and group 3 ILCs, Th17 and Th22 cells), and may also exhibit a similar plasticity (eg, the transcription factor T-bet can induce IFNγ secretion in ILC3s) 92 98. We will discuss some key aspects of these cells below.…”

“…These mice spontaneously develop colitis closely reminiscent of human UC. Specifically, TNFα secreted from CD103 − DCs in TRUC mice potentiated IL-23-induced IL-17 expression in ILCs (see below),92–94 whereby neutralisation of TNFα, IL-23p19 or IL-17A ameliorated disease 91 92. The TRUC model is a conceptually interesting model as the host genetic defects render the intestinal microbiota colitogenic, capable of transmitting disease to genetically intact mice91 92; a particular proteobacterial species, Helicobacter typhlonius , was discovered to be sufficient to cause and transfer disease 92…”

Functional Plasticity of Th17 Cells: Implications in Gastrointestinal Tract Function

“…Thus, ILC3s express RORγ t and produce IL-17 and IL-22, mimicking Th17 cells (74)]. ILCs, as Lord and collaborators first showed in the TRUC (T-bet −/− RAG2 −/− ulcerative colitis) model of colitis, mediate intestinal inflammation through IL-17 production [76]. They have also been found to be critical for IL-22 production and host defense in response to Citrobacter rodentium infection [77].…”

“…Furthermore, a functional plasticity in ILC3s and ILC1s (those expressing T-bet and producing IFN-γ , likewise Th1 cells) has also been suggested. T-bet appears to control this process, inducing IFN-γ production by RORγ t + ILCs while repressing IL-17A [76].…”