Multiple native Natural Killer cell surface receptors and their ligands (NKRs)

Natural Killer (NK) cell surface receptors and their ligands constitute a sophisticated signaling network that governs the innate immune response against infected or transformed cells [Vivier et al., Nature, 2008; PMID: 18497820]. These receptors are divided into two functional groups: activating receptors, such as NKG2D, CD16 (FcγRIIIa), and the Natural Cytotoxicity Receptors (NKp30, NKp44, NKp46), and inhibitory receptors, including Killer-cell Immunoglobulin-like Receptors (KIRs) and the NKG2A/CD94 heterodimer [Lanier, Annu Rev Immunol, 2005; PMID: 15771580]. Activating receptors recognize ligands typically induced by cellular stress or viral infection, such as MICA/B or viral hemagglutinins, while inhibitory receptors primarily recognize Major Histocompatibility Complex (MHC) class I molecules to ensure self-tolerance [Long et al., Annu Rev Immunol, 2013; PMID: 23516985]. In various diseases, particularly cancer, the balance of these signals is often disrupted, leading to immune evasion through the upregulation of inhibitory ligands like HLA-E or the loss of activating signals [André et al., Cell, 2018; PMID: 30550606]. Therapeutic strategies targeting these receptors include checkpoint inhibitors like monalizumab (anti-NKG2A) and lirilumab (anti-KIR), which aim to release the "brakes" on NK cell activity [Vey et al., Blood, 2012; PMID: 22645181]. Furthermore, monoclonal antibodies such as trastuzumab and rituximab leverage the activating receptor CD16 to induce antibody-dependent cellular cytotoxicity (ADCC) [Wang et al., Front Immunol, 2015; PMID: 26106389]. Emerging therapies also include bispecific and trispecific killer cell engagers (BiKEs and TriKEs) that simultaneously bind NK cell receptors and tumor antigens to promote targeted lysis [Felices et al., Methods Mol Biol, 2016; PMID: 27142019].

Other names

NK cell receptorsNatural Killer cell receptorsActivating and inhibitory NK receptorsNK cell checkpointsNK cell surface molecules

Modulation of NK cell activity through the blockade of inhibitory checkpoint receptors or the engagement of activating receptors to trigger cytolytic activity and cytokine release.