Protein-coding gene in the species Homo sapiens
CD226 (Cluster of Differentiation 226), PTA1 (outdated term, 'platelet and T cell activation antigen 1')[5] or DNAM-1 (DNAX Accessory Molecule-1)[5] is a ~65 kDa immunoglobulin-like transmembrane glycoprotein expressed on the surface of natural killer cells, NK T cell, B cells, dendritic cells, hematopoietic precursor cells, platelets, monocytes and T cells.[6]
DNAM-1 gene CD226 is conserved between human and mice. In humans the CD226 gene is located on chromosome 18q22.3.[7] In mice the CD226 gene is located on chromosome 18E4.
Structure
DNAM-1 is composed of three domains: an extracellular domain of 230 amino acids with two immunoglobin-like V-set domains and eight N-glycosylation sites, a transmembrane domain of 28 amino acids and a cytosolic domain of 60 amino acids containing four putative tyrosine residues and one serine residue for phosphorylation.[8]
Signaling
Upon engagement to its ligand, DNAM-1 is phosphorylated by protein kinase C. Then adhesive molecule LFA-1 crosslinks with DNAM-1 that results in recruitment of DNAM-1 to lipid rafts and promotes association with actin cytoskeleton. Cross-linking with LFA-1 also induce phosphorylation on Tyr128 and Tyr113 by Fyn Src kinase.[9]
DNAM-1 and CD244 together promotes phosphorylation of SH2 domain of SLP-76. This leads to activation of phospholipase Cγ2, Ca2+ influx, cytoskeletal reorganization, degranulation, and secretion.[8]
Function
DNAM-1 mediates cellular adhesion to other cells bearing its ligands, nectin molecule CD112 and nectin-like protein CD155,[10][11] that are broadly distributed on normal neuronal, epithelial, fibroblastic cells, dendritic cells, monocytes and on infected or transformed cells.
DNAM-1 promotes lymphocyte signaling, lymphokine secretion and cytotoxicity of NK cells and cytotoxic CD8+ T lymphocytes.[6] Cross-linking of DNAM-1 with antibodies causes cellular activation.[7]
DNAM-1 participates on platelets activation and aggregation.[8]
DNAM-1 possibly plays a role in trans-endothelial migration of NK cells because it was shown that monoclonal antibodies against DNAM-1 or CD155 inhibit this process.[9]
DNAM-1 interaction with its ligands promotes killing of immature and mature dendritic cells, is involved in the crosstalk between NK cells and T lymphocytes and can lyse activated T lymphocytes during graft versus host disease (GvHD).[8][9]
DNAM-1 also participates in the immunological synapse where is colocalized with LFA-1.[9]
DNAM-1 regulation
DNAM-1 expression on NK cells can be regulated by cell-cell interaction and by soluble factors. In human, IL-2 and IL-15 up-regulate DNAM-1 expression, whereas TGF-β, indolamine 2,3-dioxygenase and chronic exposure to CD155 can down-regulate DNAM-1 expression on NK cells.[9]
DNAM-1 and NK cells
DNAM is involved in NK cell education, differentiation, cytokine production and immune synapse formation. DNAM-1 exerts synergistic roles in NK cells regulation with three molecules that are TIGIT, CD96 and CRTAM.[9]
Cytotoxic response of NK cells might require synergistic activation from specific pairs of receptors. DNAM-1 could synergize with SLAM family member 2B4 (CD244) or with other receptors to induce full NK cell activation.[8]
DNAM-1 in cancer
The role of DNAM-1 in tumor environment was firstly described in vivo using RMA lymphoma model. In this model, enforced expression of DNAM-1 ligands CD155 and CD112 increased tumor rejection. CD155 and CD112 are expressed on the surface of a wide number of tumor cells in solid and lymphoid malignances such as lung carcinoma, primary human leukemia, myeloma, melanoma, neuroblastoma, ovarian cancer, colorectal carcinoma, and Ewing sarcoma cells.[9]
The role of DNAM-1 in the killing of tumor cells was supported with DNAM-/- mice model that was more susceptible to formation of spontaneous fibrosarcoma.[8]
It was shown that NK cells can kill leukemia and neuroblastoma cells expressing CD155 and block of CD155 or DNAM-1 results in inhibition of tumor cells lysis.[9]
In vivo, tumor cells are capable of evading DNAM-1 tumor suppressing mechanisms. Tumor cells can downregulate CD155 or CD112 to disable recognition of these DNAM-1 ligands. The other mechanism is a downregulation of DNAM-1 from the effector NK cell surface due to the chronic ligand (CD155) exposure.[9]
DNAM-1 was also used in T lymphocytes with a chimeric antigen receptors (CAR) for the treatment of cancer.[12]
DNAM-1 and infections
DNAM-1 has a relevant role in the process of recognizing virus-infected cells during early infection for example in case of cytomegalovirus infection by NK cells. DNAM-1 ligands are also expressed in antigen-presenting cells activated by toll-like receptors and CD155 might be activated by DNA-damage response as was demonstrated for human immunodeficiency virus (HIV).[8]
DNAM-1 functionality during infections may be impaired by viral immune evasion mechanisms. Viruses can downregulate production of surface CD112 and CD155 and thus avoid recognition of DNAM-1 expressed on NK cells. The other way is downregulation of DNAM-1 expressions that may occur during chronic infections.[8]
NK cells activated with interferon α can kill HCV-infected cells in a DNAM-1 dependent manner.[13]
During the bacterial infection interaction between DNAM-1 and its ligands helps to mediate the migration of leukocytes from the blood to secondary lymphoid organs or into inflamed tissues.[9]
Soluble DNAM-1
It is suggested that soluble DNAM-1 is a prognostic marker in some types of cancer and in graft-versus-host-disease and that soluble DNAM-1 might play role in pathogenesis of some autoimmune diseases such as systemic lupus erythematosus, systemic sclerosis and rheumatoid arthritis.[14]
