Natural cytotoxicity receptor ligands (NCRLs) (NCRLs)

Natural cytotoxicity receptor (NCR) ligands are a heterogeneous group of molecules, primarily proteins and glycans, that are upregulated on the surface of cells undergoing stress, viral infection, or malignant transformation (Barrow et al., 2019, Frontiers in Immunology). These ligands are specifically recognized by the natural cytotoxicity receptors—NKp46 (NCR1), NKp44 (NCR2), and NKp30 (NCR3)—which are key activating receptors expressed on Natural Killer (NK) cells (Kruse et al., 2014, Immunology Letters). Prominent examples of these ligands include B7-H6 (NCR3LG1) and BAG6 (BAT3), which are recognized by NKp30, as well as a specific isoform of MLL5 and PDGF-DD recognized by NKp44 (UniProt Q96H15; Parameswaran et al., 2018, Nature Communications). Under normal physiological conditions, these ligands are typically absent or sequestered, but their induction serves as a critical danger signal that triggers NK cell degranulation, the release of cytotoxic perforins and granzymes, and the secretion of pro-inflammatory cytokines like IFN-gamma. In oncology, these ligands are significant targets for immunotherapy; for instance, B7-H6 is often overexpressed in various cancers and can be targeted by bispecific antibodies or CAR-T cells to direct NK cell or T cell activity against the tumor (ClinicalTrials.gov). However, the therapeutic targeting of these ligands is complicated by their potential shedding into a soluble form, which can act as a decoy and inhibit NK cell function, as well as the heterogeneity of ligand expression across different tumor types.

Other names

Damage-associated NCR ligandsStress-induced NCR ligandsNKp30 ligandsNKp44 ligandsNKp46 ligandsB7-H6BAG6BAT3MLL5PDGF-DDPCNA

Activation of Natural Killer (NK) cells via natural cytotoxicity receptors (NKp30, NKp44, NKp46) to induce target cell lysis and cytokine production.