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  • br ILCs engage growth factor pathways Growth factors GFs


    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 [74] 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 SJ 172550 in smokers and patients with chronic obstructive pulmonary disease [75]. In pregnancy, maternal uterine spiral artery (SA) remodeling is essential for ensuring efficient blood flow to the developing fetus. A subset of CD49a+Eomes+ decidual NK cells (dNK) that actively secretes GFs, such as pleiotrophin and osteoglycin, have recently been described in humans and in mice. The GF-secreting function of this dNK subset was regulated by trophoblast-expressed HLA-G binding to LILRB1 (also know as ILT2) on dNK and deficiency in this subset impaired fetal development resulting in restricted fetal growth [76]. Thus, engaging with GF pathways by ILCs may operate during development, malignancy and possible also during infections with pathogens that have captured GFs or can induce their expression.
    Complement arouses ILC functions The complement system is an evolutionary ancient system of immune defense. Properdin (also known as complement factor P) is a plasma glycoprotein that binds to microbial surfaces and apoptotic cells and triggers the alternate pathway of complement that leads to the formation of the membrane attack complex and target cell lysis. Human and mouse ILC1 and a subset of ILC3 express the activating immunoreceptor NKp46 (Figure 2). Properdin binds to NKp46 and NKp46 and ILC1s were required for resistance to Neisseria meningitidis opsonized by properdin []. Since NKp46 mediates both positive and negative immunoregulation [78], it will be important to delineate the pathways regulated by the NKp46-properdin interaction in different disease models including cancer.