Finally, a bimodal model for NK cell immune function and metabolic reprogramming was proposed . metabolism, HIF-1 has an impact on this specific population of B cells. They exhibited that this HIF signaling pathway directly impacts the IL-10 production by B cells. In consequence, HIF-1 activation in B cells regulates autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) and arthritis. In summary, a deeper understanding of Ipragliflozin the HIF pathway in B cells is usually desirable and may lead to therapeutic modulation of immune responses during vaccination and autoimmune diseases. 5. Ipragliflozin The Effect of Hypoxia on Innate Lymphoid Cell Function and Metabolism 5.1. Hypoxia and ILC1 Cells Innate lymphoid cells (ILCs) are a recently discovered immune cell type, which plays an important role in lymphoid organogenesis, epithelial tissue homeostasis and defense, as well in the amplification of inflammatory responses [105,170]. Group 1 ILCs includes conventional Natural Killer (NK) cells and non-NK cell ILC1, which are characterized based on their ability to produce INF- and TNF- in response to stimulation with IL-12, IL-15, or IL-18, and expression of the transcription factors T-bet and EOMES . They play an important role in promoting responses against intracellular pathogens such as Toxoplasma gondii . NK cells are a subset of cytotoxic ILC1 with unique anticancer and antiviral activity [174,175,176,177]. NK cells carry out direct cytotoxicity of target cells via the release of Granzymes and Perforins, regulate immune responses via cytokine production (TNF and INF-) and influence DC maturation . Our recent research showed that this tumor infiltrating NK cells operate in hypoxic microenvironments and we have exhibited that HIF-1 is required for cytokine production and target cell killing upon NK cell activation, whereas the absence of HIF-1 impairs NK cell activation and effector potential. The deletion of HIF-1 in NK cells also lead to increased Ipragliflozin bioavailability of the major angiogenic cytokine vascular endothelial growth factor (VEGF), which was due to decreased numbers of tumor infiltrating NK cells that express angiostatic soluble version of Vascular Endothelial Gowth Factor Receptor 1 (VEGFR-1). Surprisingly, this resulted in non-productive angiogenesis, the creation of a high-density network of immature vessels, severe tumor hemorrhage and repressed tumor growth . In line with our data, it has been reported that hypoxia suppresses the cytotoxic potential of human NK cells against multiple myeloma, which can be restored by IL-2 activation . Moreover, it has been also shown by Sceneay et al.  that hypoxia impairs NK cell cytotoxicity. They discovered that tumor hypoxia caused the reduction in cytotoxic potential of NK cells, resulting in a decreased antitumor response that allowed metastasis formation in secondary organs. In contrast, metastatic burden was reduced when active NK cells were present in pre-metastatic lungs . Current research also Rabbit polyclonal to Relaxin 3 Receptor 1 shows that hypoxia via tumor-derived microvesicles (TD-MVs) downregulates the expression of MICA (NKG2D ligand) on tumor cells, and the activating receptor NKG2D expression on human and murine NK cells [73,74]. These tumor-derived microvesicles negatively regulate NK cells function by impaired CD107a expression via a miR-23a dependent mechanism. This is the first study to demonstrate that hypoxic tumor cells by secreting MVs can educate NK cells and impair their antitumor immune response . Interestingly, in another study it was shown that hypoxia-induced autophagy reduces breast cancer cell susceptibility to NK cell-mediated lysis. However, this process is usually reversible after targeting autophagy in tumor cells [77,78]. Finally, hypoxia has an important impact on the antiviral function of NK cells from HCV(+) patients . In analogy to Ipragliflozin na?ve human and murine T cells, resting NK cells predominantly use oxidative phosphorylation over aerobic glycolysis prior to activation . Na?ve NK cells possess.