CD244

CD244
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCD244, 2B4, NAIL, NKR2B4, Nmrk, SLAMF4, CD244 molecule
External IDsOMIM: 605554 MGI: 109294 HomoloGene: 9493 GeneCards: CD244
Orthologs
SpeciesHumanMouse
Entrez

51744

18106

Ensembl

ENSG00000122223

ENSMUSG00000004709

UniProt

Q9BZW8

Q07763

RefSeq (mRNA)

NM_001166663
NM_001166664
NM_016382

NM_018729

RefSeq (protein)

NP_001160135
NP_001160136
NP_057466

NP_061199

Location (UCSC)Chr 1: 160.83 – 160.86 MbChr 1: 171.39 – 171.44 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

CD244 (Cluster of Differentiation 244) also known as 2B4 or SLAMF4 is a protein that in humans is encoded by the CD244 gene.[5]

CD244 is a type-I transmembrane protein belonging to the signaling lymphocytic activation molecule family of receptors (SLAMF) which are expressed in different types of hematopoietic cells.[6] CD244 plays a role in the regulation of the immune system.[7]

A ligand of CD244 is CD48 (SLAMF2). CD48 also belongs to the SLAMF, it does not have an intracellular domain and it is anchored to the plasma membrane by a GPI-anchor.[6] Only these two receptors from the SLAMF mediate heterophilic interactions.[8][7]

Gene

The receptor CD244 is encoded by the CD244 gene located on the long arm of human chromosome 1.[8] Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[9] CD244 was first described in NK cells but it is also expressed in monocytes, basophils, eosinophils, mast cells, dendritic cells, and T cells.[8][10]

Structure

The receptor is composed of intracellular, transmembrane, and extracellular domains. The intracellular domain contains four intracellular tyrosine-based switch motives (ITSMs) and interacts with SH2 domain-containing proteins which are involved in the signaling and determine whether it will be activating or inhibitory.[9][6] The extracellular region of the receptor is composed of one Ig variable-like domain and one Ig constant 2-like domain.[10][6]

Function

CD244 can function as an activating or inhibitory receptor. The expression and availability of an adaptor protein SAP determine whether the signal is activating or inhibitory.[9] The inhibitory signal is mediated by binding of phosphatases SHP1, SHP2, SHIP-1 or the kinase CsK on the third ITSM.[6] Activating signaling is associated with the adaptor protein SAP.[9] SAP binds to phosphorylated tyrosines in ITSMs. Then it binds to the kinase Fyn and that enhances downstream signaling.[11] Binding of EAT2 is associated with both the activating and the inhibitory signal.[9]

CD244 is expressed in all types of NK cells,[9] and it activates their cytotoxicity and IFNγ production.[9][6] It is also expressed in a subset of effector and effector memory CD8+ T cells[9] where the activating signaling via CD244 enhances their proliferation and cytotoxic effect.[6]

Role of CD244 in viral infections

NK cells and CD8+ T cells play a crucial role in antiviral immunity. The activating signaling via CD244 leads to the enhancement of their cytolytic activity that they use for killing infected cells.[7] The expression of CD244 is increased but the expression of SAP is decreased during some chronic viral infections, such as HIV, HBV and HCV, and that is associated with the inhibitory signal and the exhaustion of CD8+ T cells.[7][9]

Role of CD244 in cancer

NK cells, T cells, dendritic cells, and myeloid-derived suppressor cells in the tumor microenvironment express CD244.[7] The type of the signal is determined by the ratio of expressed CD244 and adaptor protein SAP. However, inhibitory signaling has been shown to predominate in the tumor-associated immune cells.[10]

NK cells and CD8+ T cells use their cytolytic activity to kill tumor cells. Increased CD244 expression in these cells is associated with the inhibitory signal and the exhaustion of the cells. That leads to the impaired antitumor immunity caused by decreased cytotoxicity and proliferation of NK cells and CD8+ T cells. Dendritic cells are important antigen presenting cells. CD244 expression in dendritic cells is also associated with the inhibitory signal due to the low expression of SAP and therefore, they have decreased production of proinflammatory cytokines and reduced ability to activate NK cells and T cells. Myeloid-derived suppressor cells are suppressive cells also found in tumors. Their increased number in the tumor is associated with the progression of the disease. It is known that CD244 signaling in these cells enhances their immunosuppressive capacity resulting in the reduced immune response against tumors.[9]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000122223 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000004709 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Entrez Gene: CD244 CD244 molecule, natural killer cell receptor 2B4".
  6. ^ a b c d e f g Pahima H, Puzzovio PG, Levi-Schaffer F (July 2019). "2B4 and CD48: A powerful couple of the immune system". Clinical Immunology. 204: 64–68. doi:10.1016/j.clim.2018.10.014. PMID 30366105. S2CID 53091716.
  7. ^ a b c d e Sun L, Gang X, Li Z, Zhao X, Zhou T, Zhang S, Wang G (2021). "Advances in Understanding the Roles of CD244 (SLAMF4) in Immune Regulation and Associated Diseases". Frontiers in Immunology. 12: 648182. doi:10.3389/fimmu.2021.648182. PMC 8024546. PMID 33841431.
  8. ^ a b c van Driel BJ, Liao G, Engel P, Terhorst C (2016). "Responses to Microbial Challenges by SLAMF Receptors". Frontiers in Immunology. 7: 4. doi:10.3389/fimmu.2016.00004. PMC 4718992. PMID 26834746.
  9. ^ a b c d e f g h i j Agresta L, Hoebe KH, Janssen EM (2018). "The Emerging Role of CD244 Signaling in Immune Cells of the Tumor Microenvironment". Frontiers in Immunology. 9: 2809. doi:10.3389/fimmu.2018.02809. PMC 6279924. PMID 30546369.
  10. ^ a b c Buller CW, Mathew PA, Mathew SO (July 2020). "Roles of NK Cell Receptors 2B4 (CD244), CS1 (CD319), and LLT1 (CLEC2D) in Cancer". Cancers. 12 (7): 1755. doi:10.3390/cancers12071755. PMC 7409338. PMID 32630303.
  11. ^ Dragovich MA, Mor A (July 2018). "The SLAM family receptors: Potential therapeutic targets for inflammatory and autoimmune diseases". Autoimmunity Reviews. 17 (7): 674–682. doi:10.1016/j.autrev.2018.01.018. PMC 6508580. PMID 29729453.

Further reading

  • Vaidya SV, Mathew PA (June 2006). "Of mice and men: different functions of the murine and human 2B4 (CD244) receptor on NK cells". Immunology Letters. 105 (2): 180–184. doi:10.1016/j.imlet.2006.02.006. PMID 16621032.
  • Siu G, Strauss EC, Lai E, Hood LE (November 1986). "Analysis of a human V beta gene subfamily". The Journal of Experimental Medicine. 164 (5): 1600–1614. doi:10.1084/jem.164.5.1600. PMC 2188445. PMID 3772297.
  • Latchman Y, McKay PF, Reiser H (December 1998). "Identification of the 2B4 molecule as a counter-receptor for CD48". Journal of Immunology. 161 (11): 5809–5812. doi:10.4049/jimmunol.161.11.5809. PMID 9834056. S2CID 7819238.
  • Brown MH, Boles K, van der Merwe PA, Kumar V, Mathew PA, Barclay AN (December 1998). "2B4, the natural killer and T cell immunoglobulin superfamily surface protein, is a ligand for CD48". The Journal of Experimental Medicine. 188 (11): 2083–2090. doi:10.1084/jem.188.11.2083. PMC 2212392. PMID 9841922.
  • Tangye SG, Lazetic S, Woollatt E, Sutherland GR, Lanier LL, Phillips JH (June 1999). "Cutting edge: human 2B4, an activating NK cell receptor, recruits the protein tyrosine phosphatase SHP-2 and the adaptor signaling protein SAP". Journal of Immunology. 162 (12): 6981–6985. doi:10.4049/jimmunol.162.12.6981. PMID 10358138. S2CID 28826299.
  • Nakajima H, Cella M, Langen H, Friedlein A, Colonna M (May 1999). "Activating interactions in human NK cell recognition: the role of 2B4-CD48". European Journal of Immunology. 29 (5): 1676–1683. doi:10.1002/(SICI)1521-4141(199905)29:05<1676::AID-IMMU1676>3.0.CO;2-Y. PMID 10359122.
  • Boles KS, Nakajima H, Colonna M, Chuang SS, Stepp SE, Bennett M, et al. (July 1999). "Molecular characterization of a novel human natural killer cell receptor homologous to mouse 2B4". Tissue Antigens. 54 (1): 27–34. doi:10.1034/j.1399-0039.1999.540103.x. PMID 10458320.
  • Kubin MZ, Parshley DL, Din W, Waugh JY, Davis-Smith T, Smith CA, et al. (November 1999). "Molecular cloning and biological characterization of NK cell activation-inducing ligand, a counterstructure for CD48". European Journal of Immunology. 29 (11): 3466–3477. doi:10.1002/(SICI)1521-4141(199911)29:11<3466::AID-IMMU3466>3.0.CO;2-9. PMID 10556801.
  • Parolini S, Bottino C, Falco M, Augugliaro R, Giliani S, Franceschini R, et al. (August 2000). "X-linked lymphoproliferative disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells". The Journal of Experimental Medicine. 192 (3): 337–346. doi:10.1084/jem.192.3.337. PMC 2193227. PMID 10934222.
  • Kumaresan PR, Mathew PA (September 2000). "Structure of the human natural killer cell receptor 2B4 gene and identification of a novel alternative transcript". Immunogenetics. 51 (11): 987–992. doi:10.1007/s002510000237. PMID 11003394. S2CID 450708.
  • Watzl C, Stebbins CC, Long EO (October 2000). "NK cell inhibitory receptors prevent tyrosine phosphorylation of the activation receptor 2B4 (CD244)". Journal of Immunology. 165 (7): 3545–3548. doi:10.4049/jimmunol.165.7.3545. PMID 11034353.
  • Tangye SG, Cherwinski H, Lanier LL, Phillips JH (June 2000). "2B4-mediated activation of human natural killer cells". Molecular Immunology. 37 (9): 493–501. doi:10.1016/S0161-5890(00)00076-6. PMID 11163399.
  • Chuang SS, Pham HT, Kumaresan PR, Mathew PA (May 2001). "A prominent role for activator protein-1 in the transcription of the human 2B4 (CD244) gene in NK cells". Journal of Immunology. 166 (10): 6188–6195. doi:10.4049/jimmunol.166.10.6188. PMID 11342640.
  • Morra M, Simarro-Grande M, Martin M, Chen AS, Lanyi A, Silander O, et al. (September 2001). "Characterization of SH2D1A missense mutations identified in X-linked lymphoproliferative disease patients". The Journal of Biological Chemistry. 276 (39): 36809–36816. doi:10.1074/jbc.M101305200. hdl:2437/230556. PMID 11477068. S2CID 39889619.
  • Morra M, Lu J, Poy F, Martin M, Sayos J, Calpe S, et al. (November 2001). "Structural basis for the interaction of the free SH2 domain EAT-2 with SLAM receptors in hematopoietic cells". The EMBO Journal. 20 (21): 5840–5852. doi:10.1093/emboj/20.21.5840. PMC 125701. PMID 11689425.
  • Speiser DE, Colonna M, Ayyoub M, Cella M, Pittet MJ, Batard P, et al. (December 2001). "The activatory receptor 2B4 is expressed in vivo by human CD8+ effector alpha beta T cells". Journal of Immunology. 167 (11): 6165–6170. doi:10.4049/jimmunol.167.11.6165. PMID 11714776.
  • Chuang SS, Kumaresan PR, Mathew PA (December 2001). "2B4 (CD244)-mediated activation of cytotoxicity and IFN-gamma release in human NK cells involves distinct pathways". Journal of Immunology. 167 (11): 6210–6216. doi:10.4049/jimmunol.167.11.6210. PMID 11714782.
  • Bottino C, Parolini S, Biassoni R, et al. (2001). "X-linked lymphoproliferative disease: The dark side of 2b4 function". Progress in Basic and Clinical Immunology. Advances in Experimental Medicine and Biology. Vol. 495. pp. 63–7. doi:10.1007/978-1-4615-0685-0_9. ISBN 978-1-4613-5194-8. PMID 11774610.
  • Aoukaty A, Tan R (April 2002). "Association of the X-linked lymphoproliferative disease gene product SAP/SH2D1A with 2B4, a natural killer cell-activating molecule, is dependent on phosphoinositide 3-kinase". The Journal of Biological Chemistry. 277 (15): 13331–13337. doi:10.1074/jbc.M112029200. PMID 11815622.
  • Sivori S, Falco M, Marcenaro E, Parolini S, Biassoni R, Bottino C, et al. (April 2002). "Early expression of triggering receptors and regulatory role of 2B4 in human natural killer cell precursors undergoing in vitro differentiation". Proceedings of the National Academy of Sciences of the United States of America. 99 (7): 4526–4531. Bibcode:2002PNAS...99.4526S. doi:10.1073/pnas.072065999. PMC 123681. PMID 11917118.
  • Assarsson E, Kambayashi T, Persson CM, Ljunggren HG, Chambers BJ (February 2005). "2B4 co-stimulation: NK cells and their control of adaptive immune responses". Molecular Immunology. 42 (4): 419–423. doi:10.1016/j.molimm.2004.07.021. PMID 15607793.

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