Biology:CD226

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

CD226 (Cluster of Differentiation 226), PTA1 (outdated term, 'platelet and T cell activation antigen 1')[1] or DNAM-1 (DNAX Accessory Molecule-1)[1] is a ~65 kDa  immunoglobulin-like transmembrane glycoprotein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.[2]

DNAM-1 gene CD226 is conserved between human and mice. In humans the CD226 gene is located on chromosome 18q22.3.[3] 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.[4]

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.[5]

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.[4]

Function

DNAM-1 mediates cellular adhesion to other cells bearing its ligands, nectin molecule CD112 and nectin-like protein CD155,[6][7] 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.[2] Cross-linking of DNAM-1 with antibodies causes cellular activation.[3]

DNAM-1 participates on platelets activation and aggregation.[4]

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.[5]

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).[4][5]

DNAM-1 also participates in the immunological synapse where is colocalized with LFA-1.[5]

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.[5]

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.[5]  

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.[4]

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.[5]

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.[4]  

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.[5]

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.[5]

DNAM-1 was also used in T lymphocytes with a chimeric antigen receptors (CAR) for the treatment of cancer.[8]

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).[4]

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.[4]

NK cells activated with interferon α can kill HCV-infected cells in a DNAM-1 dependent manner.[9]

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.[5]

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.[10]

See also

References

  1. ↑ 1.0 1.1 "The role of NK cell recognition of nectin and nectin-like proteins in tumor immunosurveillance". Seminars in Cancer Biology 16 (5): 359–366. October 2006. doi:10.1016/j.semcancer.2006.07.002. PMID 16904340. 
  2. ↑ 2.0 2.1 "CD226: An Emerging Role in Immunologic Diseases". Frontiers in Cell and Developmental Biology 8: 564. 2020-07-24. doi:10.3389/fcell.2020.00564. PMID 32850777. 
  3. ↑ 3.0 3.1 "Entrez Gene: CD226 CD226 molecule". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10666. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 "DNAM-1 control of natural killer cells functions through nectin and nectin-like proteins". Immunology and Cell Biology 92 (3): 237–244. March 2014. doi:10.1038/icb.2013.95. PMID 24343663. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 "Critical roles of co-activation receptor DNAX accessory molecule-1 in natural killer cell immunity". Immunology 146 (3): 369–378. November 2015. doi:10.1111/imm.12516. PMID 26235210. 
  6. ↑ "Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule". The Journal of Experimental Medicine 198 (4): 557–567. August 2003. doi:10.1084/jem.20030788. PMID 12913096. 
  7. ↑ "Functional characterization of DNAM-1 (CD226) interaction with its ligands PVR (CD155) and nectin-2 (PRR-2/CD112)". International Immunology 16 (4): 533–538. April 2004. doi:10.1093/intimm/dxh059. PMID 15039383. 
  8. ↑ "DNAM-1-based chimeric antigen receptors enhance T cell effector function and exhibit in vivo efficacy against melanoma". Cancer Immunology, Immunotherapy 64 (4): 409–418. April 2015. doi:10.1007/s00262-014-1648-2. PMID 25549845. 
  9. ↑ "Interferon α-stimulated natural killer cells from patients with acute hepatitis C virus (HCV) infection recognize HCV-infected and uninfected hepatoma cells via DNAX accessory molecule-1". The Journal of Infectious Diseases 205 (9): 1351–1362. May 2012. doi:10.1093/infdis/jis210. PMID 22457290. 
  10. ↑ "Association of elevated serum soluble CD226 levels with the disease activity and flares of systemic lupus erythematosus". Scientific Reports 11 (1): 16162. August 2021. doi:10.1038/s41598-021-95711-2. PMID 34373559. Bibcode: 2021NatSR..1116162N. 

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.



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