• 2018-07
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  • 2019-04
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  • 2019-08
  • In addition to tissue resident stromal and myeloid cell popu


    In addition to tissue-resident stromal and myeloid cell populations, ILCs also readily engage in positive-feedback loops with myeloid doxycycline hcl recruited from the circulation. TNF-α produced by inflammatory monocytes recruited to the lungs of mice infected with Klebsiella pneumoniae markedly increased the frequency of ILCs producing IL-17, which enhanced monocyte-mediated bacterial uptake and killing []. Basophils are an important source of IL-4 and are recruited from the circulation to provide protection against helminths but may also mediate detrimental tissue functions, such as allergen-induced inflammation [38]. ILC2s express the IL-4R and IL-4 released by basophils can stimulate ILC2s to promote allergen-induced airway inflammation [39] and atopic dermatitis-like disease [40]. Notably, the genes encoding IL-33, IL-33R (ST2), TSLP, IL-4, IL-5 and IL-13 have all been linked to atopic disease [41].
    Regulation of ILC functions by cytokines Whilst many cytokines are potent drivers of ILC activation, some may also inhibit ILC functions to limit inflammatory responses or are usurped by pathogens or tumor cells to promote immunosuppression. For example, tumor-derived TGF-β can suppress NK cell functions and drive their differentiation into pro-tumorigenic ILC1 [] (Figure 1). SMAD4 has been identified as playing an unexpected role in regulating non-canonical TGF-β signaling in conventional NK cells. SMAD4-deficient NK cells unexpectedly acquired an ILC1-like gene signature and were unable to control tumor metastasis or viral infection [43]. TGF-β also impairs the development of NKp46+ ILC3 suggesting that TGF-β cross-inhibits different ILC subsets [44]. Autocrine TGF-β production has been proposed to maintain and expand a population of regulatory ILC (ILCreg) that secrete IL-10 during intestinal inflammation and can suppress the activity of ILC1s and ILC3s [45] (Figure 1). Type I IFNs (i.e. IFN-α and IFN-β), IFN-γ and IL-27 can inhibit ILC2 responses, which may be critical for limiting type 2 immunopathology following viral or bacterial infection [46, 47, 48]. Conversely, ILC2-activating cytokines, for example epithelial cell-derived IL-25/TSLP, can cross-inhibit IL-22 secretion from ILC3 suggesting that a finely tuned equilibrium exists in the maintenance of intestinal barrier immunity [49,50]. In addition to cross-inhibition, ILC subsets may autoregulate their own effector functions. For example, CCR6+ ILC3s control their abundance doxycycline hcl and the production of IL-17 and IL-22 in response to IL-23 through intercellular interactions between the TNFSF11 (RANKL) and its receptor TNFRSF11 (RANK), suggesting local cell density mediates a feedback mechanism to dampen ILC3 activity, which may represent a form of quorum sensing []. Interestingly, a polymorphism in the gene encoding RANKL is associated with Crohn’s disease [52]. ILC regulation is also accomplished through competition for cytokine availability. ILC2 and ILC3 require IL-7 for development, while ILC1 and NK cells mainly depend on IL-15 [1, 2, 3]. In an immunocompetent organism, the expansion of ILCs is limited by the presence of adaptive lymphocytes that compete for stroma-derived IL-7 and/or IL-15. In the absence of T cells, ILC3s are overstimulated by intestinal microbiota resulting in sustained IL-22 production, which, in turn, impacts lipid transport by intestinal epithelial cells and impaired lipid metabolism [53]. Conversely, ILC3 can limit homeostatic T cell proliferation by consuming IL-7 [54,55]. Similarly, MHCII+ ILC3s may induce the cell death of commensal bacteria-specific CD4+ T cells through TCR-induction of an apoptotic program in concert with sequestering IL-2 []. Uterine NK (uNK) cells are the most abundant ILC population at the feto-maternal interface during early gestation and play a significant role in the establishment and maintenance of pregnancy-related vascularization [57,58]. The interaction between TNFSF12 (also known as TWEAK) and its receptor, TNFRSF12A, (also know as Fn14) helps counterbalance the cytotoxic function of uNK cells to maintain feto-maternal tolerance necessary for successful pregnancy [59] (Figure 3).