Alternative titles; symbols
HGNC Approved Gene Symbol: CD226
Cytogenetic location: 18q22.2 Genomic coordinates (GRCh38) : 18:69,853,274-69,961,773 (from NCBI)
CD226 belongs to the immunoglobulin (Ig) superfamily and is expressed on the majority of natural killer (NK) cells, T cells, monocytes, and platelets. Through its interaction with various ligands, including LFA1 (see 153370), CD155 (PVR; 173850), and CD112 (PVRL2; 600798), CD226 plays an important role in T cell- and NK cell-mediated recognition and lysis of tumor cells (summary by Iguchi-Manaka et al., 2008).
Accessory molecules, such as LFA1, CD2 (186990), and CD8 (186910), facilitate the intercellular conjugation of cytotoxic T lymphocytes (CTLs) with target cells and transduce signals that augment or synergize with signals from the T-cell receptor (TCR; see 186880). Shibuya et al. (1996) identified a monoclonal antibody, DX11, that inhibited CTL activity of a T-cell clone that exhibited TCR-independent cytotoxicity and also cytotoxicity mediated by NK-cell clones. Flow cytometric analysis showed that the antigen recognized by DX11, DNAX accessory molecule-1 (DNAM1), was expressed on most peripheral blood T cells, NK cells, monocytes, and a subset of B cells, but not on granulocytes, erythrocytes, or on fibroblast and tumor cell lines. By affinity chromatography, micropeptide sequencing, and PCR with degenerate primers, followed by screening a T-cell cDNA library with the PCR product as probe, Shibuya et al. (1996) isolated a full-length cDNA encoding DNAM1. The predicted 336-amino acid, type I transmembrane protein is a member of the Ig superfamily and contains an 18-amino acid leader sequence; a 230-amino acid extracellular domain with 8 potential N-glycosylation sites and 2 pairs of cys residues; a 28-amino acid transmembrane domain; and a 60-amino acid cytoplasmic region with 3 potential tyrosine phosphorylation sites and a potential GRB2 (108355)-binding site. SDS-PAGE analysis showed that immunoprecipitated DNAM1 had a molecular mass of approximately 65 kD, which decreased to the predicted size of 35 kD after deglycosylation.
Using Western blot analysis, Shibuya et al. (1996) demonstrated that DNAM1 was phosphorylated after engagement by DX11. Binding analysis showed that target cells whose lysis was blocked by DX11 treatment of effector cells adhered to cells expressing DNAM1 but not to cells expressing control proteins, supporting the identification of DNAM1 as an intercellular adhesion molecule.
Shibuya et al. (1999) observed that ligation of DNAM1 on NK cells from patients with leukocyte adhesion deficiency (LAD; 116920) did not trigger cytotoxicity. Reconstituting the expression of LFA1 on the surface of these patients' cells restored the ability of anti-DNAM1 to induce cytotoxicity. Immunoblot analysis demonstrated that DNAM1 was coimmunoprecipitated from NK cells and activated but not resting T cells with CD11A (ITGAL; 153370) and CD18 (ITGB2; 600065), but not with CD11B (ITGAM; 120980) or CD11C (ITGAX; 151510). The CD18 association with DNAM1 required protein kinase C (see 176960) activation and phosphorylation of ser329 of DNAM1. Phosphorylation of tyr322 of DNAM1 was induced by anti-CD18 in stimulated T cells and was mediated by FYN (137025).
Bottino et al. (2003) immunized mice with NK-susceptible human target cells and obtained antibodies to poliovirus receptor (PVR; 173850) and nectin-2 (PVRL2; 600798). Binding analysis and flow cytometry demonstrated that both molecules bound strongly with DNAM1, but not with other activating NK receptors, including NKp46 (NCR1; 604530) and NKp30 (NCR3; 611550). Expression of PVR or PVRL2 rendered cells susceptible to enhanced lysis in a DNAM1-dependent manner that was nearly abrogated in the presence of antibody to PVR, PVRL2, or DNAM1.
By flow cytometric and immunohistochemical analysis, Reymond et al. (2004) found that PVR and nectin-2 were expressed at cell junctions on primary vascular endothelial cells. Binding of DNAM1 at endothelial junctions was abrogated by anti-PVR, but not by anti-nectin-2. Transmigration assays showed that either anti-PVR or anti-DNAM1 blocked monocyte transmigration through endothelium, with monocyte arrest at the apical surface of endothelium over intercellular junctions, suggesting that the DNAM1-PVR interaction occurs during diapedesis. Reymond et al. (2004) concluded that DNAM1 regulates monocyte extravasation via interaction with PVR.
Liu et al. (2012) generated the 1.85-angstrom crystal structure of the nectin-2 Ig-like V-set domain and showed that it bound to both the soluble ectodomain of DNAM1 and cell surface-expressed full-length DNAM1. Mutational analysis revealed that disruption of the homodimeric interface of nectin-2 led to failure of homodimer formation and loss of binding to DNAM1.
By FISH, Shibuya et al. (1996) mapped the DNAM1 gene to 18q22.3.
Iguchi-Manaka et al. (2008) found that cytotoxic T lymphocytes and NK cells from Dnam1 -/- mice were less able to lyse Dnam1 ligand-expressing tumors than wildtype cells. Dnam1 -/- mice exhibited increased tumor development and mortality following transplantation of a mouse fibrosarcoma line expressing Cd155. Dnam1 -/- mice developed significantly more Dnam1 ligand-expressing fibrosarcoma and papilloma cells in response to carcinogens than did wildtype mice. Iguchi-Manaka et al. (2008) concluded that DNAM1 plays an important role in immune surveillance of tumor development.
Using flow cytometric analysis, Tao et al. (2005) found that NKT cells from patients with active systemic lupus erythematosus (SLE; 152700) were more susceptible to apoptosis induced by anti-CD95 (TNFRSF6; 134637) than NKT cells from patients with inactive SLE or normal controls. Further analysis suggested that deficient expression of CD226 and survivin (BIRC5; 603352) in NKT cells from patients with active SLE may explain the sensitivity of these cells to apoptosis. However, in 2012, Tao et al. (2005) retracted their paper.
Bottino, C., Castriconi, R., Pende, D., Rivera, P., Nanni, M., Carnemolla, B., Cantoni, C., Grassi, J., Marcenaro, S., Reymond, N., Vitale, M., Moretta, L., Lopez, M., Moretta, A. Identification of PVR (CD155) and nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J. Exp. Med. 198: 557-567, 2003. [PubMed: 12913096] [Full Text: https://doi.org/10.1084/jem.20030788]
Iguchi-Manaka, A., Kai, H., Yamashita, Y., Shibata, K., Tahara-Hanaoka, S., Honda, S., Yasui, T., Kikutani, H., Shibuya, K., Shibuya, A. Accelerated tumor growth in mice deficient in DNAM-1 receptor. J. Exp. Med. 205: 2959-2964, 2008. [PubMed: 19029379] [Full Text: https://doi.org/10.1084/jem.20081611]
Liu, J., Qian, X., Chen, Z., Xu, X., Gao, F., Zhang, S., Zhang, R., Qi, J., Gao, G. F., Yan, J. Crystal structure of cell adhesion molecule nectin-2/CD112 and its binding to immune receptor DNAM-1/CD226. J Immun. 188: 5511-5520, 2012. [PubMed: 22547693] [Full Text: https://doi.org/10.4049/jimmunol.1200324]
Reymond, N., Imbert, A.-M., Devilard, E., Fabre, S., Chabannon, C., Xerri, L., Farnarier, C., Cantoni, C., Bottino, C., Moretta, A., Dubreuil, P., Lopez, M. DNAM-1 and PVR regulate monocyte migration through endothelial junctions. J. Exp. Med. 199: 1331-1341, 2004. [PubMed: 15136589] [Full Text: https://doi.org/10.1084/jem.20032206]
Shibuya, A., Campbell, D., Hannum, C., Yssel, H., Franz-Bacon, K., McClanahan, T., Kitamura, T., Nicholl, J., Sutherland, G. R., Lanier, L. L., Phillips, J. H. DNAM-1, a novel adhesion molecule involved in the cytolytic function of T lymphocytes. Immunity 4: 573-581, 1996. [PubMed: 8673704] [Full Text: https://doi.org/10.1016/s1074-7613(00)70060-4]
Shibuya, K., Lanier, L. L., Phillips, J. H., Ochs, H. D., Shimizu, K., Nakayama, E., Nakauchi, H., Shibuya, A. Physical and functional association of LFA-1 with DNAM-1 adhesion molecule. Immunity 11: 615-623, 1999. [PubMed: 10591186] [Full Text: https://doi.org/10.1016/s1074-7613(00)80136-3]
Tao, D., Shangwu, L., Qun, W., Yan, L., Wei, J., Junyan, L., Feili, G., Boquan, J., Jinquan, T. CD226 expression deficiency causes high sensitivity to apoptosis in NK T cells from patients with systemic lupus erythematosus. J. Immun. 174: 1281-1290, 2005. Note: Retraction: J. Immun. 188: 5800 only, 2012. [PubMed: 15661884] [Full Text: https://doi.org/10.4049/jimmunol.174.3.1281]