CD226 molecule (DNAX accessory molecule-1 receptor) (CD226 (DNAM-1))

The CD226 molecule—also known as DNAX accessory molecule-1 receptor—is a ~65 kDa immunoglobulin-like transmembrane glycoprotein expressed primarily on natural killer (NK) cells and cytotoxic T lymphocytes but also found on B cells, dendritic cells, hematopoietic precursor cells, platelets, monocytes and other immune cell types. It functions as a co-stimulatory receptor that recognizes ligands such as PVR/CD155 and NECTIN2/CD112 present on virus-infected or tumor target cells. Engagement with these ligands triggers intracellular signaling cascades involving Src family kinases like Fyn/Lyn leading to phosphorylation events that recruit adaptor proteins such as Grb2. This results in downstream activation of VAV1/PI3K/PLCG pathways promoting calcium influx and cytoskeletal reorganization necessary for cytotoxicity. Therapeutically targeting the CD226 pathway aims at enhancing antitumor immunity by boosting NK cell/T-cell-mediated killing of cancer targets through agonist antibodies like LY3435151; however clinical development has been limited due partly because its broad expression profile includes platelets which raises safety concerns regarding thrombosis risk upon systemic activation. Genetic polymorphisms within the *CD226* gene have been associated with susceptibility/resistance toward certain autoimmune diseases highlighting its central role in maintaining immune homeostasis alongside inhibitory receptors such as TIGIT which compete for shared ligands thus fine-tuning overall immune activity against tumors versus self-tissues.

Other names

DNAX accessory molecule-1DNAM-1PTA1 (platelet and T cell activation antigen 1)TLiSA1 (T lineage-specific antigen 1)CD226 antigen

- **Agonist antibodies**: Activate CD226 signaling to enhance antitumor immune responses. - **Inhibitors**: Not widely developed; most focus is on agonists. Mechanistically: Upon ligand binding to PVR/CD155 or NECTIN2/CD112 on target cells, promotes cytotoxic activity of NK cells and CTLs. Phosphorylation by Src kinases enables binding to adapter GRB2 and activation of VAV1, PI3K/PLCG pathways leading to calcium flux and cytoskeletal reorganization.