On of MHC class-I is mediated by a family of receptors termed Killer Ig-like receptors (KIRs), by the NKG2A/CD94 heterodimer and by LIR-1 (CD85j). In specific, NKG2A/CD94, expressed early during the approach of NK cell maturation, recognizes the nonclassical HLA-E molecule [1398, 1399] while KIRs, expressed at later stages of NK cell maturation, recognize allelic determinants of HLA-A -B or -C [1400, 1401]. Other nonHLA-related inhibitory receptors such as Siglec7 (CD328), PD1 (CD279), and IRP60 (CD300a) may well be expressed at the surface of NK cells (see Tables 57 and 58). In most instances, the NK receptors that mediate their activation upon binding to target cells are nonHLA-specific and recognize cell stress-induced molecules. These receptors involve NKp30, NKp44, and NKp46 (which Glycoprotein 130 (gp130) Proteins MedChemExpress constitute the all-natural cytotoxicity [NCR] loved ones), NKp80, 2B4 (CD244), and NKG2D [1402404]. Of note, activating isoforms of KIRs also exist [1405]. Even though inhibitory KIRs are characterized by immune-receptor tyrosine-based inhibition motif (ITIM) domains in their lengthy intracytoplasmic tail, the several activating receptors bear a brief intracytoplasmic tail and are related with signaling polypeptides containing immune-receptor tyrosine-based activating motifs (ITAM) domains [1406]. A fundamentalEur J Immunol. Author manuscript; obtainable in PMC 2020 July 10.Cossarizza et al.Pageactivating receptor is also CD16, the low affinity Fc receptor, which binding to IgG complexes mediates the Ab-dependent cell-cytotoxicity (ADCC). In resting conditions, the vibrant expression of CD16 is restricted to mature NK cells. Amongst peripheral NK cells, two big subsets happen to be identified on the basis from the cell surface density of CD56 molecules (neural cell adhesion molecule, N-CAM). CD56bright (CD3-CD56++CD16-/+) represent approximately ten on the circulating PB NK cells even though they prevail in secondary lymphoid Fibroblast Growth Factor 21 (FGF-21) Proteins Biological Activity organs (liver, synovial fluid and decidua). CD56dim (CD3-CD56+/- CD16++) cells are largely predominant ( 90) in PB NK cells. They derive from CD56bright NK cells, as revealed by distinctive studies in vitro (differentiation from HSC) and in vivo soon after HSC transplantation [1407, 1408]. Additionally, the existence of a third NK cell population totally lacking CD56 has been extensively demonstrated each on virus infected individuals and, much more hardly ever, on healthy donors. This population is characterized by a reduced expression of NCRs and, in in vitro research, by a poor cytotoxic activity [14091412]. 5.three.2 CD56bright NK cells: In resting circumstances all CD56bright, in contrast to CD56dim, NK cells are poorly cytolytic but secrete cytokines, mostly IFN- and TNF- and express both higher (CD25) and intermediate (CD122/CD132) affinity IL-2 receptors and c-Kit (CD117), rendering them very susceptible to IL-2 nduced cell proliferation [1413, 1414]. Additionally, CD56bright NK cells express higher levels of both CD62L [1415] and CXCR3 which, collectively with the surface expression of CCR7, dictates their preferential homing into secondary lymphoid organs [1416418] Notably, although poorly cytotoxic beneath resting conditions, CD56bright NK cells may possibly obtain cytolytic activity comparable to that of CD56dim cells upon stimulation with cytokines, like IL-2, IL-12, IL-15. Though CD56bright NK cells express CD94/NKG2A (i.e., the receptor for HLA-E) they lack KIRs. Regarding activating NK receptors, CD56bright cells express greater levels of NKp46 and NKp30 than CD56dim cells, even though CD56bright cells.