ILC3s and Intestinal Inflammatory Disorders: History
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Subjects: Immunology
Contributor:
Mingzhu Zheng

Innate lymphoid cells (ILCs) are a population of lymphoid cells that do not express T cell or B cell antigen-specific receptors. ILC3s are RORγt-expressing cells and are capable of producing IL-22 and IL-17 to maintain intestinal homeostasis. ILCs, mainly ILC3s, are located at the small intestine lamina propria (siLP). They are the first line in the gut to fight against the pathogens; therefore, their dysfunction will result in intestinal disorders such as inflammation.

  • ILC3
  • Intestinal Inflammatory Disorders
  • immune

1. Type 3 Innate Lymphoid Cells

Type 3 innate lymphoid cells (ILC3s) are the most abundant ILCs in the gut and are involved in the innate immune responses against bacterial infection and maintenance of gut microbiota composition [1][2][3][4][5][6][7][8]. ILC3s express the transcription factor RORγt and depend on IL-7 for their development [9]. Some ILC3s could up-regulate T-bet to suppress RORγt expression and become IFN-γ-expressing cells when exposed to IL-12/18 [10]. ILC3s maintain intestinal homeostasis by producing IL-22 and IL-17 [11][12][13]. There are two subsets of ILC3s based on differential expression of cell surface markers CCR6 and NCR—one is CCR6+ LTi and LTi-like cells, and the other is NCR+ ILC3s. LTi cells, recognized long before the establishment of the ILC concept, play a critical role in lymphoid organogenesis [14]. LTi cells develop and function mainly at the fetal stage, whereas LTi-like cells are generated during adulthood. LTi-like cells can also produce the ILC3 signature cytokine IL-22 and play a protective role against pathogens [13][14]. NCR+ ILC3s are NKp46+ in mice and NKp44+ in human. NCR+ ILC3s can produce IL-22 and IL-17 as well as GM-CSF [15]. In mice, NKp46+ ILC3s are T-bet dependent and can also produce IFN-γ [16][17][18].

2. ILC3-Related Intestinal Inflammatory Disorders

ILC3s are enriched in the ileum [10][19] and colon [20]. In the steady state, the major function of ILC3s is to maintain the homeostasis of the intestinal barrier and to keep the balance between gut microbiota and immune cells. Once they sense the bacterial antigen, DCs and mononuclear cells will produce a large amount of IL-23 and IL-1β, which in turn stimulate ILC3s to produce the effector cytokines IL-22, IL-17, and GM-CSF. The aryl hydrocarbon receptor (Ahr) controls the development of adult but not fetal RORγt+ ILC3s in mice. Ahr is also critical for IL-22 expression, since Ahr-deficient ILC3s produce less IL-22 [21][22][23]. Similarly, dietary vitamin A deficiency results in abnormal ILC3s, reduced IL-22 production, and susceptibility of mice to Citrobacter rodentium infection [24]. Furthermore, RORγt+NKp46+ IL-22-producing ILCs contribute to host defense during intestinal damage in murine colitis models. These cells are localized in the intestine in normal and DSS-induced colitis in the Rag2−/− mice. Interestingly, IFN-γ-producing ILC1s are decreased in RORγt-deficient Rag2−/− mice, which develop more severe colitis induced by DSS, accompanied with lower expression of REG3b and REG3c in the colon [25].
T-bet controls ILC3 cellularity but does do not drive a pathogenic role of ILC3s in mice with a conventional SPF microbiota. T-bet-deficient mice have an increase in NKp46− ILC3s accompanied with enhanced expression of RORγt and IL-7R, but independent of STAT1 or STAT4 signaling pathways. However, T-bet-deficient mice do not have a greater risk to develop spontaneous colitis [26]. A catalytic subunit of the mammalian chromatin remodeling BAF complex Brg1 (encoded by brahma-related gene 1) is known to regulate the development and function of various immune cells. When Brg1 is specifically deleted in ILC3s, the conversion of NKp46− ILC3s to NKp46+ ILC3s was blocked because of the failure of T-bet upregulation in NKp46− ILC3s [27]. Strikingly, Brg1−/−Rag1−/− ILC3s produce increased amounts of GM-CSF and develop spontaneous colitis [27].
Epithelial fucose is used as a dietary carbohydrate by many commensal bacteria, which can induce epithelial fucosylation. Goto et al. report that ILC3s induce intestinal epithelial fucosyltransferase 2 (Fut2) expression and subsequent fucosylation in mice. This induction requires the IL-22 and lymphotoxin in a commensal bacteria-dependent and -independent manner, respectively. Disruption of intestinal fucosylation results in increased susceptibility to infection by Salmonella typhimurium [28].
The activation of ILC3s has rhythm. Wang et al. report that the clock regulator REV-ERBα (encoded by Nr1d1) has the prominent and rhythmic expression in ILC3s, which is associated with rhythmic cytokine expression [29]. Development and functions of the NKp46+ ILC3 subset is markedly impaired in REV-ERBα-deficient mice, as evidenced by reduced cell number, RORγt expression, and IL-22 production. REV-ERBα also has circadian-independent impacts on ILC3 development and functions through the regulation of RORγt [29]. VIP receptor type 2 (VIPR2; also known as VPAC2) selectively expressed on ILC3s can be activated by vasoactive intestinal peptide (VIP) expressed on enteric neurons; the production of VIP triggered by food intake can limit the expression of IL-22 by ILC3s. It has also been reported that the neuroimmune circuit in the intestine dynamic promotes IL-22-mediated innate immune protection [30]. In contrast, another group has demonstrated that VIP interacts with VIPR2 expressed on intestinal ILC3s, which results in increased production of IL-22 and enhanced barrier function of the epithelium. Conversely, deficiency of VIP-VIPR2 signaling results in impaired production of IL-22 by ILC3s and animals’ susceptibility to inflammation-induced gut injury [31].
However, ILC3s function as a double-edged sword in intestinal inflammatory diseases. In the physiologic state, ILC3s maintain gut microenvironmental homeostasis through the production of IL-22, IL-17, and GM-CSF at reasonable amounts to protect gut epithelia from microbe invasion. On the other hand, in the pathological state, ILC3s may transit towards an ILC1 phenotype. These dysfunctional ILC3s may over-produce IL-22/IL-17 and IFN-γ, which leads to the progression and aggravation of IBD [32]. ILC3s also participate in intestinal allografts. ILC1s and ILC3s are present in the epithelial compartment of functional human intestinal allografts. The balance among proinflammatory and homeostatic roles of ILC subsets will determine the viability of intestinal grafts [33].
ILC3s communicate with other immune cells such as Th cell subsets in the gut. Firstly, ILC3s could negatively regulate Th17 cells. Commensal segmented filamentous bacteria (SFB) will expand in Ahr-deficient mice due to reduced IL-22, and these mice have enhanced Th17 cell differentiation. Rorcgfp/+Ahr−/− mice have a more severe reduction of ILC3s compared to Rorc+/+Ahr−/− mice and are prone to spontaneous colitis. Thus, Ahr-expressing ILCs can limit T cell-mediated experimental colitis by suppressing pathogenic Th17 cells. These data indicate an intricate balance between ILC3s and Th17 cells regulated by Ahr and microbiota [34]. Secondly, ILC3s can support Treg cell survival and/or expansion in the intestine through IL-2 to prevent chronic gut inflammation Notably, T cell-specific deletions of IL-2 do not affect Tregs in the small intestine. Unexpectedly, the dominant source of IL-2 is ILC3s, and IL-2 is induced selectively by IL-1 β. Studies show that ILC3-derived IL-2 is required for Treg maintenance and oral tolerance to dietary antigens in the gastrointestinal tract. Furthermore, Crohn’s disease patients produce less IL-2 by ILC3s in the small intestine, and this is also relevant to lower frequencies of Tregs. Thus, the protective effects of IL-2 contain the generation, maintenance, and function of Tregs, and the potential therapeutic strategy for patients with IBD is the usage of low doses of IL-2 [35]. Thirdly, Mao et al. identified that CD4+ T cells can also regulate ILC3 activation in the intestine. In WT mice, phosphorylated-STAT3 is only transiently induced by microbial colonization at the weaning stage, when CD4+ T cell-mediated immunity is still being developed to control the expanding commensal burden. By contrast, the persistent phosphorylation of STAT3 in ILC3s induced by IL-23 was observed in the absence of CD4+ T cells. As a result, the persistent IL-22 production from ILC3s in T cell-deficient mice results in impaired host lipid metabolism in the small intestine. These findings provide new insights into how innate and adaptive lymphocytes synthesize to establish steady-state commensalism and metabolic tissue homeostasis in distinct ways during normal development [36].

This entry is adapted from the peer-reviewed paper 10.3390/ijms23031856

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