Natural cytotoxicity triggering receptor 3 ligand (NKp30 ligand)

Natural cytotoxicity triggering receptor 3 (NCR3, also known as NKp30) ligands are a class of proteins that serve as critical triggers for natural killer (NK) cell activation (UniProt P14770). The primary and most studied ligand is B7-H6 (NCR3LG1), a member of the B7 family of immune-modulating proteins (Brandt et al., 2009, PubMed: 19525963). While B7-H6 is typically absent from healthy tissues, it is frequently overexpressed on the surface of various malignant cells, including those in leukemia, lymphoma, and several solid tumors (UniProt Q68D85). Other ligands include BAG6 (also known as BAT3), which can be expressed on the cell surface or released in soluble form, and certain viral proteins like the cytomegalovirus pp65 (Pogge von Strandmann et al., 2007, PubMed: 17449720; Arnon et al., 2005, PubMed: 15843547). The binding of these ligands to the NKp30 receptor initiates signaling cascades that lead to NK cell degranulation, the release of perforin and granzymes, and the production of cytokines such as interferon-gamma. In therapeutic development, B7-H6 is targeted by bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapies to direct immune responses against cancer cells. However, the shedding of soluble B7-H6 by tumor cells can act as a decoy, inhibiting NK cell function and contributing to immune evasion (Schlecker et al., 2010, PubMed: 20952657).

Other names

B7-H6NCR3LG1BAG6BAT3B7 homolog 6BCL2-associated athanogene 6pp65

Ligands bind to the NKp30 receptor on natural killer (NK) cells, leading to the phosphorylation of ITAM-containing adapter proteins (such as CD3-zeta or Fc-epsilon-RI-gamma), which triggers NK cell degranulation, target cell lysis, and the release of pro-inflammatory cytokines.