IntroductionNatural killer (NK) cells are important effectors of the innate immune system involved in the clearance of virus-infected and tumor cells. 1 The activity of NK cells is regulated by receptors with opposing functions, triggering either inhibitory or stimulatory pathways. 2 Killer inhibitory immunoglobulin-like receptors (KIRs) recognize epitopes shared by groups of human leukocyte antigen (HLA) class 1 molecules, and adequate expression of appropriate KIR ligands protects healthy "self" cells against NK cell reactivity. 3 In the absence of this inhibitory pathway, targets become susceptible to NK-mediated lysis. The stimulatory pathway is dependent on engagement of activating receptors, NKG2D, and natural cytotoxicity receptors (NCRs), which transduce signals initiated by the triggering ligands present on infected or transformed cells. 4,5 NKG2D is expressed by NK cells and by T cell receptor (TCR) ␣ ϩ CD8 ϩ and TCR ␥␦ ϩ subsets of T cells. 6,7 It recognizes several cell-surface ligands belonging to major histocompatibility complex class I chain-related (MIC) and UL16-binding protein (ULBP) protein families in humans 8,9 and H60 and Rae1 in mice. [10][11][12] MICA and MICB are generally either absent or present at low levels on normal cells, but their expression increases in response to various forms of cellular stress. Up-regulation of MICA and MICB on many human primary tumors of epithelial origin indicates that these ligands mark tumor cells for immune rejection. 13 The ULBP family of NKG2D ligands was identified by the ligands' ability to bind the cytomegalovirus (CMV) glycoprotein UL16. 9,14 Engagement of NKG2D by ULBPs induces NK cell cytotoxicity against tumor targets. 15 The expression patterns of ULBP and MIC molecules in tumor cell lines differ, 9,16 likely reflecting nonredundant functions of these NKG2D ligands.NCRs, which include NKp30, NKp44, and NKp46, are almost exclusively expressed by NK cells. 17 They function as the main activating receptors, and NCR density and NK-mediated cytolytic activity against tumor cells are correlated. 18 In virus-infected cells, viral hemagglutinins are recognized by NKp44 and NKp46. 19,20 However, no endogenous cellular NCR ligands have been identified as yet. Cross-linking of NCRs induces coupling of the signal-transducing adaptor molecules DAP12, CD3, and Fc⑀RI␥, whereas NKG2D in human cells associates with DAP10. 21,22 Use of distinct signaling components allows NKG2D to cooperate with NCRs, in particular on NCR dull NK cells, for recognition and lysis of tumor cells. 23,24 Because the susceptibility of tumors to NK-mediated lysis relies on a balance between inhibitory and triggering signals, through changes in the expression pattern and levels of receptors and their ligands, tumors can evade immune surveillance by NK cells. The online version of this article contains a data supplement.Reprints: Aleksandra Wodnar-Filipowicz, Department of Research, Experimental Hematology, Basel University Hospital, Hebelstrasse 20, CH-4031 Basel, Switzerland; e-mail...
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