Natural cytotoxicity triggering receptor 2 ligands (NKp44 ligands) (NKp44L)

NKp44 (NCR2) is a potent activating receptor expressed on activated Natural Killer (NK) cells, playing a critical role in the recognition and elimination of transformed or infected cells (UniProt O95944). The ligands for NKp44 are a heterogeneous group of molecules that are often upregulated or aberrantly expressed on the surface of tumor cells and virus-infected cells. Key identified ligands include a specific cell-surface isoform of Mixed-lineage leukemia protein 5 (MLL5) (Baychelier et al., 2013), BCL2-associated athanogene 6 (BAG6/BAT3) (Pogge von Strandmann et al., 2007), and Proliferating Cell Nuclear Antigen (PCNA) (Rosental et al., 2011), as well as various viral proteins like influenza hemagglutinin (Arnon et al., 2001). While most NKp44-ligand interactions promote NK cell activation and target cell lysis, the interaction with surface PCNA can lead to immune evasion by delivering inhibitory signals (Rosental et al., 2011). Therapeutic strategies targeting this axis include the use of NKp44-Fc fusion proteins to neutralize inhibitory ligands or the development of NKp44-based chimeric antigen receptors (CARs) and bispecific engagers to enhance NK cell-mediated anti-tumor immunity (Gaggero et al., 2018). These ligands serve as important markers for identifying cells susceptible to NK cell attack and are being explored as targets for next-generation immunotherapies.

Other names

NKp44 ligandsNCR2 ligandsMixed-lineage leukemia protein 5 (MLL5) surface isoformBCL2-associated athanogene 6 (BAG6)HLA-B-associated transcript 3 (BAT3)Proliferating cell nuclear antigen (PCNA) surface isoformNidogen-1Galectin-3HLA-DP

Activation of NK cell-mediated cytotoxicity through the engagement of the NKp44 receptor, blockade of inhibitory ligand-receptor interactions (e.g., surface PCNA), and redirection of immune effector cells to target cells expressing these ligands.