DNAM-1 geneCD226 is conserved between human and mice. In humans the CD226gene is located onchromosome 18q22.3.[7] In mice the CD226 gene is located on chromosome 18E4.
DNAM-1 is composed of three domains: an extracellular domain of 230amino acids with two immunoglobin-likeV-set domains and eight N-glycosylation sites, a transmembrane domain of 28 amino acids and acytosolic domain of 60 amino acids containing four putativetyrosine residues and oneserine residue forphosphorylation.[8]
Upon engagement to itsligand, DNAM-1 is phosphorylated byprotein kinase C. Then adhesive moleculeLFA-1 crosslinks with DNAM-1 that results in recruitment of DNAM-1 tolipid rafts and promotes association withactincytoskeleton. Cross-linking with LFA-1 also induce phosphorylation on Tyr128 and Tyr113 byFyn Src kinase.[9]
DNAM-1 mediates cellularadhesion to other cells bearing its ligands, nectin moleculeCD112 and nectin-like proteinCD155,[10][11] that are broadly distributed on normal neuronal, epithelial, fibroblastic cells, dendritic cells, monocytes and on infected ortransformed cells.
DNAM-1 participates onplatelets 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 lymphocytesduring graft versus host disease (GvHD).[8][9]
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, whereasTGF-β, indolamine 2,3-dioxygenase and chronic exposure toCD155 can down-regulate DNAM-1 expression on NK cells.[9]
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 areTIGIT,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]
The role of DNAM-1 in the killing of tumor cells was supported with DNAM-/- mice model that was more susceptible to formation ofspontaneous 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 cellslysis.[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 functionality during infections may be impaired by viralimmune 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 withinterferon 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 theblood tosecondary lymphoid organs or intoinflamed tissues.[9]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^abFuchs A, Colonna M (October 2006). "The role of NK cell recognition of nectin and nectin-like proteins in tumor immunosurveillance".Seminars in Cancer Biology.16 (5):359–366.doi:10.1016/j.semcancer.2006.07.002.PMID16904340.
Shibuya A, Campbell D, Hannum C, Yssel H, Franz-Bacon K, McClanahan T, et al. (June 1996). "DNAM-1, a novel adhesion molecule involved in the cytolytic function of T lymphocytes".Immunity.4 (6):573–581.doi:10.1016/S1074-7613(00)70060-4.hdl:2241/102273.PMID8673704.
Shibuya K, Lanier LL, Phillips JH, Ochs HD, Shimizu K, Nakayama E, et al. (November 1999). "Physical and functional association of LFA-1 with DNAM-1 adhesion molecule".Immunity.11 (5):615–623.doi:10.1016/S1074-7613(00)80136-3.hdl:2241/102003.PMID10591186.
Pende D, Bottino C, Castriconi R, Cantoni C, Marcenaro S, Rivera P, et al. (February 2005). "PVR (CD155) and Nectin-2 (CD112) as ligands of the human DNAM-1 (CD226) activating receptor: involvement in tumor cell lysis".Molecular Immunology.42 (4):463–469.doi:10.1016/j.molimm.2004.07.028.PMID15607800.
Ma D, Sun Y, Lin D, Wang H, Dai B, Zhang X, et al. (March 2005). "CD226 is expressed on the megakaryocytic lineage from hematopoietic stem cells/progenitor cells and involved in its polyploidization".European Journal of Haematology.74 (3):228–240.doi:10.1111/j.1600-0609.2004.00345.x.PMID15693793.S2CID23453162.
Storojeva I, Boulay JL, Ballabeni P, Buess M, Terracciano L, Laffer U, et al. (2005). "Prognostic and predictive relevance of DNAM-1, SOCS6 and CADH-7 genes on chromosome 18q in colorectal cancer".Oncology.68 (2–3):246–255.doi:10.1159/000086781.PMID16015041.S2CID21262033.
Ye X, Zhang Z, Jiang Y, Han X, Wang Y, Zhang M, et al. (2006). "Expression of human CD226 on T cells and natural killer cells and of soluble CD226 in plasma of HIV-1-infected Chinese patients".Viral Immunology.19 (3):576–581.doi:10.1089/vim.2006.19.576.PMID16987076.