Many studies have compared gene expression between resting and ac

Many studies have compared gene expression between resting and activated NK cells using microarray analysis. Several cytokines including IL-2, IL-8, IL-12, IL-21, and IFN-α can activate NK cells and alter multiple cellular responses, such as proliferation, cytotoxicity, and cytokine/chemokine production [69]. Microarray analysis of cytokine-induced variations

in gene expression has led to a better understanding of the molecular mechanisms underlying these responses in NK cells Kinase Inhibitor Library [6, 7, 70-72]. Microarray analysis revealed that IL-2-activated human NK cells rapidly downregulate quiescence-associated genes (FOXO3A, CDKN1B) and upregulate genes associated with cell-cycle progression and proliferation (cyclins, CDKs, E2f TFs, and PCNA) [73]. Moreover, numerous genes that enhance immune responses were upregulated, including activating receptors (KLRC1, KLRC3), death receptor ligands (FasL, TNFSF10), cytokine receptors (IL2RG, IL18RAB, IL27RA), chemokine receptors (CX3CR1, CCR5, CCR7), members of secretory pathways (DEGS1, FKBP11, SLC3A2), and the TF T-bet [73]. Furthermore, systematic analysis showed that IL-2-activated CD16+ pNK Atezolizumab mouse cells overexpress several genes (including OX40 ligand, CD86, Tim3, and galectins) that have been shown to enable NK cells to directly crosstalk with

other innate and adaptive immune effector cells, such as DCs and

T cells [42]. Moreover, these activated 3-mercaptopyruvate sulfurtransferase CD16+ pNK cells acquired immunoregulatory functions, secreted more immune effector molecules (such as granzyme A, granzyme B, and CTLA1), and displayed enhanced cell cytotoxicity [42]. Another study by Hodge et al. compared the gene expression patterns between resting and cytokine-stimulated NK-92 cells, and the comparison included stimulation by IL-2 alone, IL-2 plus IL-18, and IL-2 plus IL-12 [74]. Interestingly, the majority of these altered transcripts were cytokines, chemokines, and chemokine receptors. The authors showed that activated NK-92 cells upregulate immune effectors (including perforin, IFN-γ, and IL-10). Meanwhile, after activation, NK-92 cells downregulate expression of the CXCR3 chemokine receptor and thus significantly reduced chemotaxis in the presence of its ligand, IFN-γ-inducible protein 10 (CXCL10, also known as IP-10) [74]. NK cells are also activated through stimulation of their activating NK receptors, which can be modeled experimentally by cross-linking these receptors with soluble agonist mAbs. The Ly49 receptors are type II C-type lectin-like membrane glycoproteins that recognize MHC class I and MHC class I like proteins on target cells in mice [75].

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