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  • br Cytokines potent mediators of ILC function The


    Cytokines – potent mediators of ILC function The different ILC players are portrayed in three categories, ILC1, ILC2 and ILC3, based on the cytokines they produce and transcription factors (TFs) that guide their differentiation [8] (Figure 1). Cytokines are the most extensively studied stimuli for ILCs. Seminal studies have shown that each ILC group can be activated via specific cytokine receptors that trigger the secretion of signature cytokine modules (Figure 2). For example, T-bet+ ILC1 produce IFN-γ in response to IL-12, IL-15 and IL-18, facilitating the control of intracellular pathogens by classical macrophage activation [1, 2, 3]. ILC2, which express high levels of GATA3, respond to IL-25, IL-33 and Thymic Stromal Lymphopoietin (TSLP) by secreting interleukin-5 (IL-5), IL-9, and IL-13 that promote alternative macrophage activation, eosinophilia, and goblet cell hyperplasia to limit helminth infections [9, 10, 11, 12]. Rorγt+ ILC3 react to IL-23 and IL-1β stimulation by producing IL-17 and IL-22 that trigger epithelial defense mechanisms and granulocytic responses to combat extracellular bacterial and fungal infections [1, 2, 3]. Collectively, these functional ILC modules mirror the functional polarizations of CD4+ T helper (Th)1, Th2, and Th17 cells. Natural Killer (NK) Liquidambaric acid are also innate lymphocytes that produce IFN-γ but are distinct from ILC1 because they specialize in the cytolysis of malignant or pathogen-infected cells and are therefore considered innate counterparts of cytotoxic CD8+ T cells. The lymphoid tissue-inducer (LTi) cells that spark lymphoid tissue organogenesis during development are Rorγt+ and produce IL-17 and IL-22; therefore, LTi are frequently categorized as ILC3, but may represent a different lineage that emerges from the common lymphoid progenitor before ILCs [13].
    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 cells 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].