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Tissue/microenvironment shaping NK cells.

Different microenvironments can also re-shape the function and phenotypic characteristics of NK cells and thus contribute to their diversity. This concept was illustrated in a recent study in which tr-NK cells differed from PBNK cells in their expression of nutrient transporters, thus providing evidence for how tr-NK cells are required to adapt to different tissue microenvironments [19]. This transformation is also evident in tumour microenvironments where there are factors that reduce NK cell activation, such as higher concentrations of transforming growth factor-β (TGF-β), interleukin (IL)-10, IL-6, prostaglandin E2 (PGE2) and others [20]. Collectively, these secreted proteins can downregulate NK cell activation and function. Supporting this notion, tumour-resident NK cells, but not PBNK cells, express higher levels of co-inhibitory molecules, TIGIT and Tim-3 [21]. Conversely, the phenotypic plasticity of NK cells also enables them to restore their functional state in patients whose cancers are in remission [22]. NK cells being influenced by their microenvironments is further supported by the development of memory-like NK cells following exposure to specific conditions including cytokines, haptens and pathogens [23]. For example, studies have long shown that human cytomegalovirus (HCMV) infections can re-shape NK biology to expand and generate subsets of NK cells that express the activating receptor CD94/NKG2C, within which reside adaptive or memory-like NK cells [24]. In addition, these memory-like NK cells can produce higher levels of IFN-γ compared to naïve NK cells and can persist long after the infection is resolved [25, 26]. HCMV infections can also epigenetically imprint NK cells by remodelling their IFNG locus for increased accessibility and transcription of IFN-γ [27]. Overall, these studies illustrate the diversity of NK biology between and within microenvironments that cannot be captured by studies of PBNK cells.

Overview of the major discoveries on tissue-resident natural killer (NK) cells. (a) Liver-resident NK cells, at steady state, are found to express high levels of immune checkpoint inhibitors (i.e., LAG-3, PD-L1) which enables them to maintain liver immunotolerance [56]. When faced with an infection, liver-resident NK cells can lyse infected cells and produce high levels of IFN-γ. Although, at high levels of liver inflammation, liver-resident NK cells can also downregulate their production of IFN-γ to limit tissue damage [53]. It is still unclear whether this is a form of functional adaptation, impairment or both. (b) Decidual NK cells are well known to be tolerogenic due to the endosomal signalling of HLA-G. For the first time, researchers demonstrated that decidual NK cells can respond and lyse CMV-infected cells [79]. The mechanism underlying their functional shifts remains unclear. (c) Gut-resident NK cells were recently shown to be more cytolytic during infancy than adulthood [102]. Researchers described this decreased cytolytic activity as a mechanism of immunotolerance to the development of the microbiome.