CD58 molecule
Identifiers
SymbolCD58
Alt. symbolsLFA3
NCBI gene965
HGNC1688
OMIM153420
RefSeqNM_001779
UniProtP19256
Other data
LocusChr. 1 p13
Search for
StructuresSwiss-model
DomainsInterPro

CD58, or lymphocyte function-associated antigen 3 (LFA-3), is a cell adhesion molecule expressed on Antigen Presenting Cells (APCs), particularly macrophages, and other tissue cells.[1][2][3]

CD58 binds to CD2 (LFA-2) [4][5] on T cells and is important in strengthening the adhesion and recognition between the T cells and Professional Antigen Presenting Cells, facilitating signal transduction necessary for an immune response. This adhesion occurs as part of the transitory initial encounters between T cells and Antigen Presenting Cells before T cell activation, when T cells are roaming the lymph nodes looking at the surface of APCs for peptide:MHC complexes the T-cell receptors are reactive to.

Polymorphisms in the CD58 gene are associated with increased risk for multiple sclerosis.[6] Genomic region containing the single-nucleotide polymorphism rs1335532, associated with high risk of multiple sclerosis, has enhancer properties and can significantly boost the CD58 promoter activity in lymphoblast cells. The protective (C) rs1335532 allele creates functional binding site for ASCL2 transcription factor, a target of the Wnt signaling pathway.[7]

CD58 plays a role in the regulation of colorectal tumor-initiating cells (CT-ICs). Thus, cells that express CD58 have become a cell of interest in tumorigenesis.[8] Mutations of CD58 have been linked to immune evasion observed in some lymphomas and studies are underway to analyze how its involvement directly affects classical Hodgkin lymphoma (cHL).[9]

Introduction

CD58, lymphocyte-function antigen 3 (LFA-3), is a glycoprotein that plays a vital role in the body's immune response. The natural ligand to CD58, CD2, is most commonly found on the surfaces of both T cells and Natural Killer cells (T/NK cells).[3] During an immune response, the interactions between the CD2 and CD58 glycoproteins allows for the activation and proliferation of both T and Natural Killer cells (T/NK cells), enhancing cell adhesion.[3] Furthermore, upon activation, a succession of intracellular signaling within T and Natural Killer cells and other target cells occurs, enhancing further cell recognition.[3] Overall, CD58-CD2 interactions are intricate and involved in a variety of immune regulatory responses, including antiviral, inflammation in numerous autoimmune diseases, and immune rejections in organ transplants.[3]

CD58 is expressed on a variety of different cells, including hematopoietic and nonhematopoietic cells.[10] More specifically, CD58 is expressed on cell surfaces, allowing for effector-target adhesion sequentially to antigen recognition.[11] This adhesion allows for proper T cell activation via correct cell signaling.

CD58 and CD2 interaction

The composition of CD2 and CD58 share many similarities. Both extracellular domains have similar amino acid sequences which aid in cell adhesion.[12] This allows for a high affinity of the extracellular amino-terminal sequence on CD2 to bind with CD58, which has a capacity to bind to CD2 on T cells, on target cells.[12][13] For a regulatory T cell to become activated, the recognition of an antigen located within a major histocompatibility complex (MHC) protein by the TcR, or T cell receptor, is insufficient.[14] Proliferation of regulatory T cells requires the TcR recognition and other co-stimulatory signals.[15] The binding of CD2-CD58 allows for the formation of a co-stimulatory signal, contributing to further regulatory T cell proliferation and regulation of T cell responses via signaling transduction.[15][16]

Structure and localization of CD58

The CD58 glycoprotein can be found in two different protein isoforms, each on the cell surface.[17] These include transmembrane and GPI-anchored form.[17] It has been found that in both isoforms, CD58 is able to interact with a variety of different kinases, and is not dependent on only one form.[17] Rather, each isoform is able to associate more effectively with different kinases.[18] Each form, transmembrane and GPI-anchored, can be found in different parts of the cell membrane. The GPI-anchored isoform is mostly found in lipid rafts while the transmembrane isoform is mainly found in nonraft domains.[18] Despite this, the transmembrane CD58 form can trigger independent signaling without the need for the GPI-anchored isoform.[18] Transmembrane CD58 has a structure that consists of six N-linked glycosylation sites in the extracellular domain, a hydrophobic transmembrane domain, and finally a short cytoplasmic domain.[19] GPI-anchored CD58 has a similar extracellular domain, but no hydrophobic transmembrane domain or cytoplasmic domain.[19] Rather, it is linked to the cell membrane via a GPI tail. It is estimated that the CD58 structure is made of approximately 44-68% carbohydrate.[19] The structure of CD58 also plays a role in cell adhesion. A study found that effective cell adhesion was dependent on the density of CD58.[20] Comparing the GPI-anchored and transmembrane isoforms, the GPI-anchored is much more efficient during cell adhesion, and on average, takes much less time than the transmembrane isoform.[20] Regardless, the structure of both the GPI-anchor and transmembrane CD58 are crucial in overall function. While the GPI-anchor enhances cell adhesion, the transmembrane isoform is more efficient in cell signal transduction.[3]

Multiple sclerosis

Multiple Sclerosis (MS) is autoimmune disease that effects the central nervous system (CNS). In an individual with MS, the immune system attacks the myelin sheath, which are crucial for covering nerve fibers and allowing proper communication with the brain and the rest of the body.[21] A genomic association study suggested that there is a risk of developing MS in individuals with allelic variation in the CD58 gene coding region.[22] Further research done on the topic suggested that there is a strong association betweenCD58 single-nucleotide polymorphism (SNP) rs12044852 and the onset of MS.[23] Another study focused on the (SNP) rs1414273 in the microRNA-548ac stem-loop region of the CD58 gene.[24] More specifically, the SNP was found to have an influence on Drosha cleavage activity, which can cause uncoupling of the expression of CD58 and microRNA-548ac production.[24] The data from the study also showed carriers of the allele rs1414273 showed an overall decrease in CD58 mRNA levels.[24] However, the carriers of the allele did exhibit an increase in the levels of hsa-miR-548ac.[24] There is an influence between CD58 and susceptibility to MS. On a similar note, a genome wide association study found that the SNP rs1335532 was associated with a decrease in the susceptibility of developing MS.[25] In addition, it was found that in individuals with MS had an increase in CD58 mRNA.[25] This was because the region where rs1335532 resides had certain properties that increased the activity of CD58 in lymphoblasts.[25] The protective rs1335532 allele also targeted the Wnt signaling pathway by creating a binding site for ASCL2, a transcription factor and target of the Wnt signaling pathway.[25] In immune cells like monocytes and primary B-cells, the Wnt signaling pathway activation causes an increase in CD58 promotor activity via a strong binding site of ASCL2.[25] A reduced expression of CD58 is a possible risk for developing MS.

Rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease that mainly affects an individual's joints, but can affect and cause problems in different tissues.[26] A study that used enzyme-linked immunosorbent assay (ELISA) to measure sCD58 (soluble form of CD58) in individuals with RA and normal controls (NC) to determine if there was a correlation between sCD58 levels and RA.[27] It was found that sCD58 levels were significantly lower in the individuals with RA compared to those in the control (NC).[27] The sCD58 levels in the synovial fluid (SF) of the individuals with RA were also lower than the control subjects.[27] A decrease in sCD58 production could cause a decrease in CD2-CD58 adhesion, leading to an increase in T cells.[28] Continued inflammation would also be an effect of the decrease in sCD58.[28]

References

  1. ↑ Barbosa JA, Mentzer SJ, Kamarck ME, Hart J, Biro PA, Strominger JL, Burakoff SJ (April 1986). "Gene mapping and somatic cell hybrid analysis of the role of human lymphocyte function-associated antigen-3 (LFA-3) in CTL-target cell interactions". Journal of Immunology. 136 (8): 3085–91. doi:10.4049/jimmunol.136.8.3085. PMID 3514752. S2CID 22866345.
  2. ↑ Wallich R, Brenner C, Brand Y, Roux M, Reister M, Meuer S (March 1998). "Gene structure, promoter characterization, and basis for alternative mRNA splicing of the human CD58 gene". Journal of Immunology. 160 (6): 2862–71. doi:10.4049/jimmunol.160.6.2862. PMID 9510189. S2CID 8489739.
  3. 1 2 3 4 5 6 Zhang, Yalu; Liu, Qiaofei; Yang, Sen; Liao, Quan (2021-06-08). "CD58 Immunobiology at a Glance". Frontiers in Immunology. 12: 705260. doi:10.3389/fimmu.2021.705260. ISSN 1664-3224. PMC 8218816. PMID 34168659.
  4. ↑ Selvaraj P, Plunkett ML, Dustin M, Sanders ME, Shaw S, Springer TA (1987). "The T lymphocyte glycoprotein CD2 binds the cell surface ligand LFA-3". Nature. 326 (6111): 400–3. Bibcode:1987Natur.326..400S. doi:10.1038/326400a0. PMID 2951597. S2CID 4334290.
  5. ↑ Wang JH, Smolyar A, Tan K, Liu JH, Kim M, Sun ZY, et al. (June 1999). "Structure of a heterophilic adhesion complex between the human CD2 and CD58 (LFA-3) counterreceptors". Cell. 97 (6): 791–803. doi:10.1016/S0092-8674(00)80790-4. PMID 10380930. S2CID 6264220.
  6. ↑ De Jager PL, Baecher-Allan C, Maier LM, Arthur AT, Ottoboni L, Barcellos L, et al. (March 2009). "The role of the CD58 locus in multiple sclerosis". Proceedings of the National Academy of Sciences of the United States of America. 106 (13): 5264–9. Bibcode:2009PNAS..106.5264D. doi:10.1073/pnas.0813310106. PMC 2664005. PMID 19237575.
  7. ↑ Mitkin NA, Muratova AM, Korneev KV, Pavshintsev VV, Rumyantsev KA, Vagida MS, et al. (October 2018). "Protective C allele of the single-nucleotide polymorphism rs1335532 is associated with strong binding of Ascl2 transcription factor and elevated CD58 expression in B-cells". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1864 (10): 3211–3220. doi:10.1016/j.bbadis.2018.07.008. PMID 30006149.
  8. ↑ Xu S, Wen Z, Jiang Q, Zhu L, Feng S, Zhao Y, et al. (March 2015). "CD58, a novel surface marker, promotes self-renewal of tumor-initiating cells in colorectal cancer". Oncogene. 34 (12): 1520–31. doi:10.1038/onc.2014.95. PMID 24727892. S2CID 22035160.
  9. ↑ Schneider M, Schneider S, Zühlke-Jenisch R, Klapper W, Sundström C, Hartmann S, et al. (October 2015). "Alterations of the CD58 gene in classical Hodgkin lymphoma". Genes, Chromosomes & Cancer. 54 (10): 638–45. doi:10.1002/gcc.22276. PMID 26194173. S2CID 28291445.
  10. ↑ Krensky, A. M.; Sanchez-Madrid, F.; Robbins, E.; Nagy, J. A.; Springer, T. A.; Burakoff, S. J. (August 1983). "The functional significance, distribution, and structure of LFA-1, LFA-2, and LFA-3: cell surface antigens associated with CTL-target interactions". Journal of Immunology. 131 (2): 611–616. doi:10.4049/jimmunol.131.2.611. ISSN 0022-1767. PMID 6345670. S2CID 24722957.
  11. ↑ Krensky, A. M.; Robbins, E.; Springer, T. A.; Burakoff, S. J. (May 1984). "LFA-1, LFA-2, and LFA-3 antigens are involved in CTL-target conjugation". Journal of Immunology. 132 (5): 2180–2182. doi:10.4049/jimmunol.132.5.2180. ISSN 0022-1767. PMID 6201533. S2CID 11856034.
  12. 1 2 Sewell, W. A.; Palmer, R. W.; Spurr, N. K.; Sheer, D.; Brown, M. H.; Bell, Y.; Crumpton, M. J. (1988). "The human LFA-3 gene is located at the same chromosome band as the gene for its receptor CD2". Immunogenetics. 28 (4): 278–282. doi:10.1007/BF00345506. ISSN 0093-7711. PMID 2458315. S2CID 11197336.
  13. ↑ Selvaraj, P.; Plunkett, M. L.; Dustin, M.; Sanders, M. E.; Shaw, S.; Springer, T. A. (March 26 – April 1, 1987). "The T lymphocyte glycoprotein CD2 binds the cell surface ligand LFA-3". Nature. 326 (6111): 400–403. Bibcode:1987Natur.326..400S. doi:10.1038/326400a0. ISSN 0028-0836. PMID 2951597. S2CID 4334290.
  14. ↑ Bierer, B. E.; Hahn, W. C. (August 1993). "T cell adhesion, avidity regulation and signaling: a molecular analysis of CD2". Seminars in Immunology. 5 (4): 249–261. doi:10.1006/smim.1993.1029. ISSN 1044-5323. PMID 7693022.
  15. 1 2 Van Seventer, G. A.; Shimizu, Y.; Horgan, K. J.; Luce, G. E.; Webb, D.; Shaw, S. (July 1991). "Remote T cell co-stimulation via LFA-1/ICAM-1 and CD2/LFA-3: demonstration with immobilized ligand/mAb and implication in monocyte-mediated co-stimulation". European Journal of Immunology. 21 (7): 1711–1718. doi:10.1002/eji.1830210719. ISSN 0014-2980. PMID 1711977. S2CID 352060.
  16. ↑ Miller, G. T.; Hochman, P. S.; Meier, W.; Tizard, R.; Bixler, S. A.; Rosa, M. D.; Wallner, B. P. (1993-07-01). "Specific interaction of lymphocyte function-associated antigen 3 with CD2 can inhibit T cell responses". The Journal of Experimental Medicine. 178 (1): 211–222. doi:10.1084/jem.178.1.211. ISSN 0022-1007. PMC 2191085. PMID 7686212.
  17. 1 2 3 Itzhaky, D.; Raz, N.; Hollander, N. (1998-05-01). "The glycosylphosphatidylinositol-anchored form and the transmembrane form of CD58 associate with protein kinases". Journal of Immunology. 160 (9): 4361–4366. doi:10.4049/jimmunol.160.9.4361. ISSN 0022-1767. PMID 9574540. S2CID 16730539.
  18. 1 2 3 Ariel, Ortal; Kukulansky, Tova; Raz, Nava; Hollander, Nurit (June 2004). "Distinct membrane localization and kinase association of the two isoforms of CD58". Cellular Signalling. 16 (6): 667–673. doi:10.1016/j.cellsig.2003.08.015. ISSN 0898-6568. PMID 15093607.
  19. 1 2 3 Wallner, B. P.; Frey, A. Z.; Tizard, R.; Mattaliano, R. J.; Hession, C.; Sanders, M. E.; Dustin, M. L.; Springer, T. A. (1987-10-01). "Primary structure of lymphocyte function-associated antigen 3 (LFA-3). The ligand of the T lymphocyte CD2 glycoprotein". The Journal of Experimental Medicine. 166 (4): 923–932. doi:10.1084/jem.166.4.923. ISSN 0022-1007. PMC 2188720. PMID 3309127.
  20. 1 2 Chan, P. Y.; Lawrence, M. B.; Dustin, M. L.; Ferguson, L. M.; Golan, D. E.; Springer, T. A. (October 1991). "Influence of receptor lateral mobility on adhesion strengthening between membranes containing LFA-3 and CD2". The Journal of Cell Biology. 115 (1): 245–255. doi:10.1083/jcb.115.1.245. ISSN 0021-9525. PMC 2289925. PMID 1717480.
  21. ↑ "Multiple sclerosis - Symptoms and causes". Mayo Clinic. Retrieved 2023-04-18.
  22. ↑ De Jager, Philip L.; Baecher-Allan, Clare; Maier, Lisa M.; Arthur, Ariel T.; Ottoboni, Linda; Barcellos, Lisa; McCauley, Jacob L.; Sawcer, Stephen; Goris, An; Saarela, Janna; Yelensky, Roman; Price, Alkes; Leppa, Virpi; Patterson, Nick; de Bakker, Paul I. W. (2009-03-31). "The role of the CD58 locus in multiple sclerosis". Proceedings of the National Academy of Sciences of the United States of America. 106 (13): 5264–5269. Bibcode:2009PNAS..106.5264D. doi:10.1073/pnas.0813310106. ISSN 1091-6490. PMC 2664005. PMID 19237575.
  23. ↑ Torbati, Sara; Karami, Fatemeh; Ghaffarpour, Majid; Zamani, Mahdi (2015). "Association of CD58 Polymorphism with Multiple Sclerosis and Response to Interferon ß Therapy in A Subset of Iranian Population". Cell Journal. 16 (4): 506–513. doi:10.22074/cellj.2015.505. ISSN 2228-5806. PMC 4297489. PMID 25685741.
  24. 1 2 3 4 Hecker, Michael; Boxberger, Nina; Illner, Nicole; Fitzner, Brit; Schröder, Ina; Winkelmann, Alexander; Dudesek, Ales; Meister, Stefanie; Koczan, Dirk; Lorenz, Peter; Thiesen, Hans-Jürgen; Zettl, Uwe Klaus (February 2019). "A genetic variant associated with multiple sclerosis inversely affects the expression of CD58 and microRNA-548ac from the same gene". PLOS Genetics. 15 (2): e1007961. doi:10.1371/journal.pgen.1007961. ISSN 1553-7404. PMC 6382214. PMID 30730892.
  25. 1 2 3 4 5 Mitkin, Nikita A.; Muratova, Alisa M.; Korneev, Kirill V.; Pavshintsev, Vsevolod V.; Rumyantsev, Konstantin A.; Vagida, Murad S.; Uvarova, Aksinya N.; Afanasyeva, Marina A.; Schwartz, Anton M.; Kuprash, Dmitry V. (October 2018). "Protective C allele of the single-nucleotide polymorphism rs1335532 is associated with strong binding of Ascl2 transcription factor and elevated CD58 expression in B-cells". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1864 (10): 3211–3220. doi:10.1016/j.bbadis.2018.07.008. ISSN 1879-260X. PMID 30006149. S2CID 51625452.
  26. ↑ "Rheumatoid Arthritis (RA) | Arthritis | CDC". www.cdc.gov. 2020-07-27. Retrieved 2023-04-19.
  27. 1 2 3 Hoffmann, J. C.; Räuker, H. J.; Krüger, H.; Bayer, B.; Zeidler, H. (1996). "Decreased levels of a soluble form of the human adhesion receptor CD58 (LFA-3) in sera and synovial fluids of patients with rheumatoid arthritis". Clinical and Experimental Rheumatology. 14 (1): 23–29. ISSN 0392-856X. PMID 8697653.
  28. 1 2 Hoffmann, J. C.; Bayer, B.; Zeidler, H. (June 1996). "Characterization of a soluble form of CD58 in synovial fluid of patients with rheumatoid arthritis (RA)". Clinical and Experimental Immunology. 104 (3): 460–466. doi:10.1046/j.1365-2249.1996.41749.x. ISSN 0009-9104. PMC 2200442. PMID 9099931.
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