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  • In contrast to inflammatory cytokines TGF


    In contrast to inflammatory cytokines, TGF-β has immunosuppressive properties yet is also important for tissue imprinting immune cell function during development [23]. Salivary gland (SG) ILCs, in addition to liver and intestinal intraepithelial ILC1, express markers denoting tissue residency and TGF-β imprinting, such as CD49a, TRAIL and CD73 [24] (Figure 2). TGF-β promotes the differentiation of SG ILC1 by suppressing the TF Eomes required for the differentiation of conventional NK ppy (Figure 1). Moreover, TGF-β imprinting of SG ILC1 was found to be concurrent with SG development [24] (Figure 3). The lymphotoxin (LT)-pathway is a critical mechanism by which fetal LTi regulate lymphoid organogenesis, such as lymph nodes and Peyer’s patches (PP), during development and polymorphisms in the genes encoding LTα are linked to several phenotypes that contribute to metabolic syndrome [25]. Fetal ILC precursors (ftILCPs) with the potential for differentiation into either ILC1s, ILC2s or ILC3s reside in the intestine during the development of PP [26]. The ftILCPs aggregate at PP anlagen in a LTα-dependent manner forming a localized source for ILC populations (Figure 3). Thus, the LT-pathway may link the host immune response, microbiota, and metabolic syndrome [25]. Using Il7-lineage trace mice, a subset of ICAM+VCAM+ murine fetal lymphoid tissue organizer (LTo) cells that express LTβR and RANKL were shown to give rise to a population of adult marginal reticular cells (MRCs) that form a dedicated stromal niche for resident ILC3 in secondary lymphoid tissues throughout life [27]. A population of PDGFRα+gp38+ mesenchymal cells provides an optimal microenvironment for the terminal differentiation of fetal liver-derived ILC2s in peripheral tissues. However, the specific factors produced by these mesenchymal cells that can promote terminal ILC2 differentiation and maturation were not identified [28]. Macrophages and DCs are prominent sensors of the tissue environment due to their extensive expression of pattern recognition receptors and can also instruct ILC acquisition of specialized tissue-specific functions. For example, ILC3 are located in close spatial proximity to intestinal CX₃CR1+ mononuclear phagocytes, which produce more IL-23 and IL-1β than conventional CD103+ DC, and are more efficient in stimulating IL-22 production by ILC3 [29]. Similarly, CD11c+ DCs expressing IL-18 are found in close proximity to ILC3s in human tonsils. IL-18 cooperated with an ILC3 survival factor, IL-15, to induce proliferation of human ILC3s, and production of IL-22 [30]. Cross-talk between ILC3 and intestinal macrophages is critical for intestinal homeostasis. Microbiota-driven IL-1β production by intestinal macrophages stimulated ILC3-mediated release of GM-CSF, which acted on DCs and macrophages to maintain colonic Treg numbers [31]. Interestingly, TNFSF15 (also know as TL1A) is selectively expressed by human intestinal mononuclear phagocytes and is associated with ulcerative colitis and Crohn’s disease. TNFSF15 binds to TNFRSF25 (also know as DR3) to enhance IL-23 and IL-1β-induced production of IL-22 and GM-CSF by ILC3 [29]. TNFSF15 also promotes the expansion, survival, and functionality of ILC2s. Consequently, Tnfrsf25−/− mice fail to control gut helminthic infections or mount ILC2 responses in the lung after nasal challenge with papain [32]. In another example of interplay between TNF-TNFR superfamily members regulating ILCs, TNFRSF14 (HVEM) binding to TNFSF14 (LIGHT) promotes IFN-γ production from ILC3s and protection from Yersinia enterocolitica [33]. Recent studies using IL-22 reporter mice suggest that high IL-22 expression is a unique feature of LTi cells, which colocalize with a population of activated macrophages constitutively positive for IL-23p40 in the isolated lymphoid follicles of the intestine that appear at weaning and are maintained by the microbiota [34]. The interaction of LTαβ on LTi cells with LTβR expressed on DCs in cryptopatches promotes an amplification loop resulting in IL-23 secretion by DCs and enhanced IL-22 production by LTi during Citrobacter rodentium infection [35,36].