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Cellular sources of cytokines that trigger and maintain ILC Many studies are now beginning to address the cellular sources and tissue microenvironmental conditions that may imprint ILC identity and trigger their responses during development and in either steady state or pathogenic tissue conditions [14, 15, 16]. Interactions of epithelial and mesenchymal tissues with ILCs are therefore important during fetal and adult life (Figure 3). In addition to providing crucial structural support and barrier protection, epithelial and stromal teva 3026 australia are prominent tissue-resident sensors and potent drivers of ILC function. Thus, ILCs readily form positive feedback loops by sensing cytokines released by specialized epithelial cells and fibroblasts. For example, tuft cells are chemosensory epithelial cells that line the intestine and respiratory tract and provide an innate source of IL-25 to drive type 2 immune responses. Tuft cells can sense succinate fermented by intestinal parasites to drive an IL-25-ILC2-IL-13-dependent immune circuit that controls parasite infections and initiates intestinal remodeling [17,18]. Conversely, tuft cells are targets for norovirus infection in the intestine and IL-25 induced upon co-infection with parasites or helminths can promote type 2 cytokines that induce tuft cell proliferation and perpetuate norovirus infection [19]. IL-33 is a member of the IL-1 family that is released by damaged epithelial and endothelial cells that induces strong ILC2 activation and resistance to helminth infections or promotes allergen-induced lung and skin inflammation [1]. Interestingly, IL-33 derived from islet mesenchymal cells activated the expression of IL-13 and GM-CSF by ILC2, which induced retinoic acid (RA) production by macrophages and dendritic cells (DCs) that signaled β cells to increase insulin secretion. IL-33 injections rescued islet function in obese mice with a defective IL-33-ILC2 axis, suggesting that immunometabolic crosstalk between IL-33, ILC2s, and myeloid cells regulates insulin production in pancreatic islets []. IL-1α is another inflammatory cytokine produced by virus-infected intestinal epithelial cells that stimulates IL-22 production from ILC3 and enhances the clearance of rotavirus [21]. Fibroblastic reticular cells (FRC) are stromal cells in lymphoid tissues that express IL-15 and are essential for ILC1 maintenance in Peyer’s patches and mesenteric lymph nodes. FRCs can sense the intestinal microflora through Toll-like receptors (TLRs), which suppress the secretion of IL-15. Thus, FRC-specific deficiency of the TLR signaling adaptor Myd88 elicited increased IL-15 production and ILC1 hyperactivation that accelerated clearance of an enteropathogenic virus yet also precipitated severe intestinal inflammatory disease [22]. 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 cells (Figure 1). Moreover, TGF-β imprinting of SG ILC1 was found to be concurrent with SG development [24] (Figure 3).