Natural killer cell p44-related protein ligands (NKp44L) (NKp44L)

Natural killer cell p44-related protein ligands (NKp44L) are a heterogeneous group of endogenous and exogenous molecules that bind to the Natural Cytotoxicity Receptor 2 (NCR2/NKp44), an activating receptor primarily expressed on activated Natural Killer (NK) cells (Vieillard et al., 2005, PNAS). These ligands include a diverse array of proteins such as a tumor-associated isoform of Mixed-Lineage Leukemia protein 5 (MLL5), the nuclear chaperone BAG6 (also known as BAT3), and the DNA replication protein PCNA, which can be translocated to the cell surface in malignant cells (Rosental et al., 2011, Immunity; Pogge von Strandmann et al., 2007, Blood). The interaction between NKp44 and its ligands is a key component of the induced-self recognition system, where stressed, infected, or transformed cells upregulate these molecules to trigger NK cell-mediated destruction. However, the system is complex; while ligands like BAG6 typically promote NK cell activation, surface-expressed PCNA can deliver inhibitory signals that allow tumors to evade immune surveillance (Gaggero et al., 2022, Front. Immunol.). NKp44L is significantly upregulated in various solid and hematological cancers and during viral infections, notably HIV-1, where its expression on CD4+ T cells correlates with disease progression (Vieillard et al., 2010, J. Exp. Med.). Therapeutic development focuses on utilizing NKp44-Fc fusion proteins or monoclonal antibodies to either block inhibitory interactions or enhance the activation of NK cells against ligand-positive targets.

Other names

NCR2 ligandsCD336 ligandsNKp44LMLL5 isoformBAG6BAT3PCNA (surface-expressed)Nidogen-1PDGF-DDHLA-DP (HLA-DPB1*04:01)

Modulation of NK cell activity through binding to the NCR2/NKp44 receptor