T-bet controls intestinal mucosa immune responses via repression of type 2 innate lymphoid cell function
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Innate lymphoid cells (ILCs) play a crucial role in early mucosal immune defence, inflammation and tissue remodelling.1 Based on the transcription factors that govern their differentiation, function and signature cytokine production, mature IL-7Rα+ ILCs can be classified into three groups: ILC1s, which express T-bet and produce IFNγ and TNFα; ILC2s that express high levels of GATA-3 and produce type 2 cytokines; and ILC3s that express RORγt, produce IL-22 and IL-17,1 and can be further subdivided based on the expression of the chemokine receptor CCR6 and the natural cytotoxicity receptor NKp46 or NCR, encoded by the gene Ncr1. 2 In addition to ILC1s, T-bet is co-expressed with NKp46 in NCR+ ILC3s (in which it is co-expressed with RORγt) and cNK cells.2,3 T-bet is essential for ILC development, as germline deletion of Tbet results in a complete loss of NCR+ ILCs,2,4 and it is also involved in NCR+ ILC function. The first description of this came from studies in the TRUC mouse (T-bet−/− x RAG2−/− ulcerative colitis), which develop spontaneous colitis dependent on IL-17- producing ILC3s.5 Furthermore, within the CCR6− ILC3 subset, Tbet expression is required for CCR6-/low ILC3s differentiation into NCR+ ILC3s and subsequent IFNγ production.2,6,7 T-bet is also induced in human and murine ILC2s, resulting in the production of IFNγ. 8–11 Among several cytokines, IL-12 and IL-18 appear to be the main driver of these effects, however their pathophysiological relevance is still unknown. The absence of ILC1s in T-bet−/− mice is linked to increased susceptibility to enteric infections.2,6,12–14 We have previously reported the phenotype of TRUC mice that develop spontaneous colitis, which is dependent on IL-17-producing CCR6+ ILC3s in the absence of adaptive immunity.5 Increased frequency of inflammatory ILC1s has also been found in inflamed intestine from Crohn’s disease patients.6,13,15 However, whether T-bet expression in ILCs drives protective or pathogenic mucosal immune responses in the presence of an intact immune system still needs to be elucidated. Importantly, we have recently shown that alterations in T-bet binding are critical determining factors in driving mucosal inflammatory diseases in humans.16 Here, we define a previously unrecognised role for T-bet in ILC2 function and its significance in the control of helminth infection and the pathogenesis of dextran sodium sulphate (DSS)-induced colitis. In the presence of an intact immune system, specific targeting of T-bet in ILCs results in the development of protective intestinal ILC2 responses. Crucially, T-bet regulates responsiveness of the intestinal ILC pool to IL-7 signalling. Therefore, we propose that T-bet acts as a key molecular regulator, controlling both pathogenic and protective immune responses in the intestine in a context-dependent manner.
AuthorsGarrido-Mesa, N; Schroeder, J-H; Stolarczyk, E; Gallagher, AL; Lo, JW; Bailey, C; Campbell, L; Sexl, V; MacDonald, TT; Howard, JK
- Immune Systems 
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