CD226 (DNAX accessory molecule-1) [DNAM-1] (DNAM-1 (also known as CD226))

CD226 (DNAM-1) is a ~65 kDa nectin-like immunoglobulin superfamily transmembrane glycoprotein receptor expressed on NK cells, CD8+ T cells, subsets of CD4+ T cells, myeloid cells, platelets, and others[1][3][7]. It contains two extracellular IgV-like domains, a transmembrane segment, and a cytosolic tail with phosphorylation sites[1]. Upon engagement with its ligands CD155 (PVR) and CD112 (Nectin-2), DNAM-1 triggers phosphorylation-dependent signaling (including Erk, Akt, PLCγ2 pathways), Ca2+ influx, cytoskeletal reorganization, and degranulation, and secretion, enhancing natural cytotoxicity[3][5]. DNAM-1 is crucial for NK/T-cell–mediated tumor cell killing and participates in monocyte transendothelial migration via endothelial CD155 at junctions[3][5]. Clinically relevant observations include frequent expression on AML blasts with functional cytokine responses and associations with patient outcomes, underscoring its role in cancer immunosurveillance and its therapeutic relevance in the CD112/CD155 immune checkpoint axis, including interplay with TIGIT blockade[7][3].

Other names

CD226DNAM-1 (DNAX accessory molecule-1)PTA1 (platelet and T cell activation antigen 1; outdated)DNAX accessory molecule-1

Immune activating receptor engagement: DNAM-1 binding to ligands CD155 (PVR) and CD112 (Nectin-2) promotes NK/T-cell activation, cytotoxicity, cytokine secretion via phosphorylation events and downstream Erk, Akt, PLCγ2, Ca2+ signaling, cytoskeletal reorganization, and degranulation[3][5]. Adhesion-mediated transmigration: DNAM-1–PVR interaction facilitates monocyte diapedesis across endothelium[5]. Therapeutic context: In checkpoint therapy settings targeting TIGIT (an inhibitory receptor for the same ligands), intact DNAM-1 signaling on CD8+ T cells is required for anti-tumor effects; thus, drugs that relieve inhibition in the CD155/CD112 axis can function partly via DNAM-1 co-stimulation[3].