page_title: Innate lymphoid cell
section_title: Intestinal mucosa
hierarchical_section_title: Innate lymphoid cell / Function / Intestinal mucosa
caption_attribution_description: English: ILCs in the intestinal mucosa.
context_page_description: Innate lymphoid cells are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors. In response to pathogenic tissue damage, ILCs contribute to immunity via the secretion of signalling molecules, and the regulation of both innate and adaptive immune cells. ILCs are primarily tissue resident cells, found in both lymphoid, and non- lymphoid tissues, and rarely in the peripheral blood. They are particularly abundant at mucosal surfaces, playing a key role in mucosal immunity and homeostasis. Characteristics allowing their differentiation from other immune cells include the absence of regular lymphoid morphology, rearranged antigen receptors found on T cells and B cells, and phenotypic markers usually present on myeloid or dendritic cells.
  Based on the difference in developmental pathways, phenotype, and signalling molecules produced, in 2013, ILCs were divided into three groups: 1, 2 and 3, however, after further investigation, we now appreciate five distinct subsets within these groups: NK cells, ILC1s, ILC2s, ILC3s, and LTi cells.
context_section_description: Intestinal ILCs are exposed to dietary, microbial, and endogenous metabolites. ILC homing to the small intestine is mediated by α4β7 integrin, and the receptor CCR9. ILC2s express CCR9 in the bone marrow, so can directly home to the intestine, however, retinoic acid is required to allow CCR9 expression on ILC1s, and ILC3s.
  ILCs facilitate maintenance of barrier integrity in the intestine, protecting from various bacteria and viral infections. ILC3s are the most abundant subset present in both the adult and foetal intestine. The distribution of ILCs in the intestine changes during development, and they are unevenly distributed throughout the segments of the gastro-intestinal tract. This distribution to different niches within the intestine is mediated through distinct signalling cascades. In humans, approximately 70% of the intestinal ILCs are NCR+, and 15% are NCR-.
  ILC3s directly interact with bacterial flora, creating a network between the microbiota, and the host, favouring homeostasis. ILC3s restrict colonization of multiple unbeneficial bacteria in the gut, via secretion of IL-22, stimulating epithelial cells to produce antimicrobial peptides. The IL-22 production is induced due to the production of IL-23 and IL-1β by macrophages and DCs, and it promotes mucosal layer healing. For example, IL-22 can promote repair of intestinal damage after chemotherapy or radiotherapy. ILC3s regulate the containment of commensal bacteria in the lumen, allowing it to be exposed to lamina propria phagocytes, leading to T cell priming. Although they can present antigens, via MHC class II receptors, ILCs lack co-stimulatory molecules, and therefore play a role in T cell anergy, promoting tolerance to beneficial commensals. The relationship between ILC3s, and T cells in the gut is therefore crucial for maintaining homeostasis, as in the absence of ILC3s, there could be uncontrolled T cell activation. In addition, microbiota play a role in fine tuning IL-22 production by ILC3s, for example, segmented filamentous bacteria in the ileum regulate IL-22 production and allow differentiation of Th17 cells.
  ILC3s interact with the enteric nervous system to maintain intestinal homeostasis, as in response to bacteria, glial cells in the lamina propria secrete neurotrophic factors, which through the neuroregulatory receptor RET, induce IL-22 production by ILC3s.
  Dendritic cells can also produce IL-23 during pathogen induced stress, also activating ILC3s allowing production of IL-22. One of the mechanisms by which IL-22 regulates microbiota present in the gut is through the glycosylation patterns of epithelial cells. IL-22, and lymphotoxin expression by ILC3s controls expression of fucosyltransferase 2, which allows fucosylation of epithelial cells, providing a nutrient source for the luminal bacteria.   
  AHR ligands from diet or microbiota are recognised by immune cells, regulating ILC development and NK cell functions in the intestine. In response to tryptophan metabolites, AhR signalling maintains IL-22 expression and intestinal homeostasis. Retinoic acid, produced by dendritic cells, promotes the expression of gut homing receptors on ILC1s, and ILC3s, and enhances ILC3 function, by upregulating RORγt, and IL-22. There is also crosstalk between macrophages and ILC3s, via RORγt driven GM-CSF production, that is dependent on microbial signalling, and the production of IL-1β by macrophages. A deficiency in dietary vitamin A results in abnormally small numbers of ILC3s, and therefore a reduction of IL-22 production, and higher susceptibility to infection. Conversely, retinoic acid suppresses ILC2 proliferation by down regulating IL-7Ra, and deprivation of vitamin A has been shown to enhance ILC2- mediated resistance to helminth infection in mice. ILC3s therefore form a network of interactions to maintain intestinal homeostasis, between the microbiome, intestinal epithelium, neuro-glial cells, and other immune cells. 
  LTi cells are present in Peyer’s Patches, and lymphoid follicles, interacting with B cells facilitating IgA production, which promotes 
caption: ILCs and some of their key roles in the intestinal mucosa, allowing maintenance of intestinal homeostasis, via their associated cytokines and effector cells.
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