br Cytokine impact on ILC fate Increasing evidence
Cytokine impact on ILC fate Increasing evidence shows that ILC2 and ILC3 may convert into ILC1-like Ivacaftor benzenesulfonate clinical by downregulating either GATA3 or RORγt, respectively, upregulating T-bet and gaining the capacity for IFN-γ production [60,61]. This process, often referred to as ‘ILC plasticity’, may be important to fine tune ILC function to a changing microenvironment (Figure 1). The magnitude and the duration of cytokine stimulation plays an important role in ILC plasticity. For example, IL-23 strongly induces IL-22 secretion by ILC3 [62,63]. However, sustained exposure to IL-23 can facilitate ILC3 to ILC1 conversion. IL-23 activates STAT4 in ILC3, which drives T-bet expression . In humans, ILC3 also develop into ILC1-like cells upon in vitro culture with recombinant IL-2 or IL-15 , recombinant IL-12 , or IL-12-producing CD14+ intestinal DCs . RA and IL-23-producing CD14− DCs induced the reverse conversion of ILC1s into ILC3s , although this reverse conversion has not been established in vivo in mice. ILC2 also display functional plasticity in response to IL-12. Activation with IL-1β and IL-12 or IL-33 plus TSLP and IL-12 (but not by IL-12 alone) renders ILC2 responsive to type I polarization by upregulating T-bet and IL-12R [,67,68,69]. Consistent with this pathway, patients with Mendelian susceptibility to mycobacterial disease fail to generate IFN-γ-producing ILC1 from ILC2s due to a deficiency in IL-12Rβ1 . The strength of IL-1β signaling has also been shown to influence ILC2 plasticity. Strong IL-1β signaling upregulated the expression of IL-12R and conversion of ILC2 into ILC1, whereas low-dose IL-1β signaling favored type 2 polarization in ILC2 . ILC2 endowed with functional features of ILC3 have also been reported. Systemic injection of IL-25 led to the generation of ‘inflammatory ILC2’ (iILC2) from a Klrg1Hi progenitor cell that in addition to type 2 cytokines expressed RORγt and the signature ILC3 cytokine IL-17 and contributed to protection against Nippostrongylus brasiliensis and Candida albicans  (Figure 1). IL-2 signaling in lung ILC2s promotes cell survival/proliferation and serves as a cofactor for the production of type 2 cytokines . Conversely, IL-2 and RA signaling in combination with other as yet unidentified in vivo factors can enhance the development of a distinct subset of alternatively activated lung ILC2 that produce IL-10 (termed ILC210), which downregulate pro-inflammatory genes and are associated with reduced eosinophil recruitment to the lung  (Figure 1). Thus, the magnitude and duration of ILC stimulation by tissue cytokines combined with signals specific to the tissue microenvironment may be a critical factor in regulating the functional plasticity of ILCs in different tissues particularly during inflammatory conditions [14,15].
ILCs engage growth factor pathways Growth factors (GFs) are important for a variety of cellular and developmental processes and GF signaling pathways are commonly subverted in cancer. NKp44 is an activating immunoreceptor expressed on human activated NK cells, ILC1 and ILC3 (Figure 2). NKp44 was found to bind to PDGF-DD , a GF secreted by platelets, endothelial and tumor cells (Figure 3) that can promote angiogenesis, stromal reaction and tumor growth through PDGFRβ signaling. PDGF-DD engagement of NKp44 triggers IFN-γ and TNF-α secretion from NK cells and ILC1 and TNF-α secretion from ILC3 that induced tumor cell growth arrest in vitro and in vivo . The ability of ILCs to engage in GF surveillance through NKp44 is a new immunological paradigm that remains to be fully explored. Interestingly, transforming viruses encode PDGF homologues and a PDGFD polymorphism is associated with IFN-γ levels in humans  suggesting that GF surveillance pathways may have been driven by selective pressure imposed by transforming viruses . GF sensing by ILCs may also regulate important developmental processes. For example, human and fetal mouse ILC3s that display LTi activity and express neuropilin receptor 1 (NRP1) are located in near high endothelial venules. VEGF-A binds to NRP1 and serves as a chemotactic factor for lung-resident NRP1+ ILC3, suggesting these cells may play a role in the initiation of ectopic pulmonary lymphoid aggregates in smokers and patients with chronic obstructive pulmonary disease .