CD226 antigen (DNAX Accessory Molecule-1) (DNAM-1)

CD226 antigen, commonly known as DNAX Accessory Molecule-1 (DNAM-1), is a 65 kDa type I transmembrane glycoprotein and a member of the immunoglobulin superfamily [UniProt: Q15762]. It is constitutively expressed on the surface of Natural Killer (NK) cells, CD8+ T cells, and other immune subsets, where it functions as a potent activating receptor [PubMed: 15905536]. DNAM-1 mediates cellular adhesion and triggers cytotoxic effector functions by interacting with its ligands, CD155 (PVR) and CD112 (Nectin-2), which are frequently upregulated on the surface of various tumor cells and virus-infected cells [NCBI: Gene 10666]. In the context of adoptive cell therapy, the presence and functional integrity of DNAM-1 on infused NK cells are critical for effective tumor recognition and the subsequent release of lytic granules [PubMed: 30305454]. The DNAM-1 signaling pathway is a major focus in oncology because it is often antagonized by inhibitory receptors like TIGIT and CD96, which compete for the same ligands with higher affinity. Consequently, therapeutic strategies often involve blocking these inhibitory checkpoints to enhance DNAM-1-mediated activation of infused NK cells, thereby overcoming immune evasion in the tumor microenvironment [ClinicalTrials.gov].

Other names

CD226PTA1TLiSA1DNAX accessory molecule 1Platelet and T cell activation antigen 1

DNAM-1 (CD226) acts as an activating receptor on NK cells. Upon binding to its ligands CD155 (PVR) or CD112 (Nectin-2) on target cells, it undergoes phosphorylation of its cytoplasmic tail at Tyr322, which recruits Fyn and Lck kinases. This initiates a signaling cascade involving PLC-gamma-1 and Vav-1, leading to actin reorganization, immunological synapse formation, and the release of cytotoxic granules containing perforin and granzymes [PubMed: 15905536, UniProt: Q15762].