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CD80

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CD80
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesCD80,B7, B7-1, B7.1, BB1, CD28LG, CD28LG1, LAB7, CD80 molecule
External IDsOMIM:112203;MGI:101775;HomoloGene:3804;GeneCards:CD80;OMA:CD80 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

941

12519

Ensembl

ENSG00000121594

ENSMUSG00000075122

UniProt

P33681

Q00609

RefSeq (mRNA)

NM_005191

NM_009855
NM_001359898

RefSeq (protein)

NP_005182

NP_033985
NP_001346827

Location (UCSC)Chr 3: 119.52 – 119.56 MbChr 16: 38.28 – 38.32 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The Cluster of differentiation 80(alsoCD80andB7-1) is a B7, type I membrane protein[5]in theimmunoglobulin superfamily,with an extracellular immunoglobulin constant-like domain and a variable-like domain required for receptor binding. It is closely related toCD86,another B7 protein (B7-2), and often works in tandem. Both CD80 and CD86 interact withcostimulatory receptorsCD28,CTLA-4(CD152) and the p75 neurotrophin receptor.[6][7]

Structure

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CD80 is a member of theB7family, which consists of molecules present atAPCsand their receptors present on theT-cells.[7]CD80 is present specifically onDC,activatedB-cells,andmacrophages,but alsoT-cells.[7][8]CD80 is also atransmembraneglycoproteinand a member of theIg superfamily.[7]It is composed of 288amino acids,and its mass is 33kDa.[8]It consists of two Ig-like extracellular domains (208 AA), a transmembrane helical segment (21 AA), and a short cytoplasmic tail (25 AA).[7][8][9]The Ig-like extracellular domains are formed by single V-type and C2-type domains.[7][6][10]It is expressed as bothmonomersordimers,but predominantly dimers.[7][10][11]These two forms exist in dynamicequilibrium.[12]

CD80 shares 25% of sequences withCD86;however, CD80 has a ten-fold higheraffinityforCD28andCTLA-4thanCD86.Moreover, CD80 interacts with its ligand with faster binding kinetics and slower dissociation constants thanCD86.Both human CD80 and CD86 are located atchromosome 3;the exact region is 3q13.3-q21.[7]

HumanandmurineCD80 share approximately 44% of sequences. Also both human and murine CD80 are able to cross-react with both human and murine CD28. This indicates that the binding site of CD80 is conserved.[7][12]

Function

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CD80 can be found on the surface of variousimmune cells,includingB-cells,monocytes,or T-cells, but most typically atantigen-presenting cells(APCs) such asdendritic cells.[6][7][13]CD80 has a crucial role in modulating T-cell immune function as a checkpoint protein at theimmunological synapse.[14]

CD80 is the ligand for the proteinsCD28(for autoregulation and intercellular association) andCTLA-4(for attenuation of regulation and cellular disassociation) found on the surface ofT-cells.[6][13]Interaction of CD80 with CD28 triggerscostimulatorysignals and results in enhanced and sustained T-cell activation. In contrast, contrary interaction of CD80 with CTLA-4 inhibits parts of T-cell effector function. These twoligandsare structurally homologous, and they compete with each other forbinding sites.[14]However, the bond with CTLA-4 has up to 2500 fold higheraviditythan with CD28.[7]This illustrates that inhibitory interaction with CTLA-4 is predominant.[14]

CD80 binds toCD28andCTLA-4with loweraffinityand fast binding kinetics (Kd= 4 μM for CD28 and 0.42 μM for CTLA-4), allowing for quick interactions between the communicating cells.[15]These interactions result in an important costimulatory signal in theimmunological synapsebetweenantigen-presenting cells,B-cells,dendritic cellsandT-cellsthat result in T and B-cell activation, proliferation and differentiation.[11]

When stimulated by CD80,T helper cellspreferentially differentiate intoTh1 cells.[11]CD80 is an essential component indendritic celllicensing andcytotoxic T-cellactivation. When the major histocompatibility complex class II (MHC class II)-peptide complex on adendritic cellinteracts with the receptor on aT helper cell,CD80 is up-regulated, licensing thedendritic celland allowing for interaction between thedendritic cellandCD 8+T-cellsviaCD28.This helps to signal the T-cell differentiation into acytotoxic T-cell.[13][16]The expression of CD80, as well asCD86,is increased by the presence ofmicrobesandcytokines,which is the consequence of the presence of microbes. This mechanism ensures that costimulatory molecules forT-cellsare present at the right time.[7]

CD80, often in tandem withCD86,plays a large and diverse role in regulating both theadaptiveand theinnate immune system.As mentioned above, this protein is crucial for immune cell activation in response topathogens.The interaction of CD80 with CD28, together withTCRandMHCinteraction, results in activation of nuclear factor‐κB (NF-ⲕB), mitogen‐activated protein kinase (MAPK), and the calcium‐calcineurin pathway. These changes initiate the production of numerous factors,cytokines,andchemokinesby T-cells. Noteworthy is the production of interleukin 2 (IL-2) as well as ɑ-chain ofCD25(which is a receptor of IL-2),CD40 ligand,tumor necrosis factor‐α (TNFα), TNF‐β, and interferon‐γ (IFN‐γ). T-cells also increase the production ofmacrophage inflammatory proteins1α and 1β (MIP‐α1 and MIP‐1β) and preventapoptosisby induction of anti-apoptotic protein expression (e.g.,Bcl‐XandBcl‐2).[14][17][18][19][20]CD80 interaction withCD28also further stimulatesdendritic cells,enhancingcytokineproduction, specificallyIL-6,a pro-inflammatory molecule.[21][22]Neutrophilscan also activatemacrophageswith CD80 viaCD28.[22]Last but not least, the interaction of CD80 and CD28 enhances cell‐cycle progression by upregulating the expression levels ofD‐cyclin.[14]

In contrast to the stimulatory interaction withCD28,CD80 also regulates the immune system through an inhibitory interaction withCTLA-4.Dendritic cellsare suppressed by a CTLA-4-CD80 interaction,[22]and this interaction also promotes the suppressive effects ofregulatory T cells,which can prevent an immune response toself-antigen.[18]

In addition to interactions withCD28andCTLA-4,CD80 is also thought to interact with a separate ligand onNatural Killer cells,triggering the Natural Killer cell-mediated cell death of the CD80 carrier.[23]CD80 may also play a role in the negative regulation of effector and memory T-cells. If the interaction between anantigen-presenting celland aT-cellis stable enough, the T-cell can remove the CD80 from the antigen-presenting cell by a mechanism dubbedtrans-endocytosis.Under the right conditions, this transfer of the CD80 may induce T-cellapoptosis.[24]Finally, CD80 signaling on activatedB-cellsmay regulate antibody secretion duringinfection.[25]

Another ligand of CD80 is programmed death-ligand 1 (PD‐L1), expressed on the surface of T-cells, B-cells, DCs, and macrophages. This interaction is inhibiting and causes a reduction in T-cell activation as well as reduction of cytokine production. Its dissociation constant with CD80 is between the CD28 and CTLA-40 (Kd = 1.4 μM).[14][26]

Clinical significance

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The complicated role CD80 plays in immune system regulation presents an opportunity for CD80 interactions to go rogue in various diseases. The up-regulation of CD80 has been linked to variousautoimmune diseases,includingmultiple sclerosis,[27]systemic lupus erythematosus[28]andsepsis[29](which may partly be due to over-active T-cells), and CD80 has also been shown to help spread ofHIVinfection in the body.[30]CD80 is also linked to variouscancers,though some experience CD80 induced tolerance via possibleregulatory T-cellinteraction.[31]Others experience inhibited growth andmetastasis-related to CD80 up-regulation,[32]further exemplifies the complicated role CD80 plays.

The triggering ofNatural Killer cell-mediated death via CD80 interactions has been explored as possible cancerimmunotherapyby inducing CD80 expression on tumor cells.[23]

See also

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References

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  1. ^abcGRCh38: Ensembl release 89: ENSG00000121594–Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000075122–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. ^McKusick, V. A., & Converse, P. J. (2016, August 05). CD80 Antigen; CD80. Retrieved May 29, 2019
  6. ^abcdPeach RJ, Bajorath J, Naemura J, Leytze G, Greene J, Aruffo A, Linsley PS (September 1995)."Both extracellular immunoglobin-like domains of CD80 contain residues critical for binding T cell surface receptors CTLA-4 and CD28".The Journal of Biological Chemistry.270(36): 21181–7.doi:10.1074/jbc.270.36.21181.PMID7545666.
  7. ^abcdefghijklMir MA (2015). "Introduction to Costimulation and Costimulatory Molecules".Developing Costimulatory Molecules for Immunotherapy of Diseases.Elsevier: 1–43.doi:10.1016/b978-0-12-802585-7.00001-7.ISBN978-0-12-802585-7.
  8. ^abc"CD80 - T-lymphocyte activation antigen CD80 precursor - Homo sapiens (Human) - CD80 gene & protein".www.uniprot.org.Retrieved2021-06-09.
  9. ^Abbas AK (2021).Cellular and molecular immunology.Elsevier.ISBN978-0-323-75749-2.OCLC1173994133.
  10. ^abBhatia S, Edidin M, Almo SC, Nathenson SG (April 2006). "B7-1 and B7-2: similar costimulatory ligands with different biochemical, oligomeric and signaling properties".Immunology Letters.104(1–2): 70–5.doi:10.1016/j.imlet.2005.11.019.PMID16413062.
  11. ^abcBhatia S, Edidin M, Almo SC, Nathenson SG (October 2005)."Different cell surface oligomeric states of B7-1 and B7-2: implications for signaling".Proceedings of the National Academy of Sciences of the United States of America.102(43): 15569–74.Bibcode:2005PNAS..10215569B.doi:10.1073/pnas.0507257102.PMC1266120.PMID16221763.
  12. ^abIkemizu S, Gilbert RJ, Fennelly JA, Collins AV, Harlos K, Jones EY, et al. (January 2000)."Structure and dimerization of a soluble form of B7-1".Immunity.12(1): 51–60.doi:10.1016/s1074-7613(00)80158-2.PMID10661405.
  13. ^abcOwen JA, Punt J, Stranford SA, Jones PP, Kuby J (2013).Kuby Immunology(7th ed.). New York: W.H. Freeman and Company.
  14. ^abcdefChen R, Ganesan A, Okoye I, Arutyunova E, Elahi S, Lemieux MJ, Barakat K (March 2020). "Targeting B7-1 in immunotherapy".Medicinal Research Reviews.40(2): 654–682.doi:10.1002/med.21632.PMID31448437.S2CID201748060.
  15. ^van der Merwe PA, Bodian DL, Daenke S, Linsley P, Davis SJ (February 1997)."CD80 (B7-1) binds both CD28 and CTLA-4 with a low affinity and very fast kinetics".The Journal of Experimental Medicine.185(3): 393–403.doi:10.1084/jem.185.3.393.PMC2196039.PMID9053440.
  16. ^Fujii S, Liu K, Smith C, Bonito AJ, Steinman RM (June 2004)."The linkage of innate to adaptive immunity via maturing dendritic cells in vivo requires CD40 ligation in addition to antigen presentation and CD80/86 costimulation".The Journal of Experimental Medicine.199(12): 1607–18.doi:10.1084/jem.20040317.PMC2212806.PMID15197224.
  17. ^Snanoudj R, Frangié C, Deroure B, François H, Créput C, Beaudreuil S, et al. (September 2007)."The blockade of T-cell co-stimulation as a therapeutic stratagem for immunosuppression: Focus on belatacept".Biologics: Targets and Therapy.1(3): 203–13.PMC2721321.PMID19707331.
  18. ^abZheng Y, Manzotti CN, Liu M, Burke F, Mead KI, Sansom DM (March 2004)."CD86 and CD80 differentially modulate the suppressive function of human regulatory T cells".Journal of Immunology.172(5): 2778–84.doi:10.4049/jimmunol.172.5.2778.PMID14978077.
  19. ^Boise LH, Minn AJ, Noel PJ, June CH, Accavitti MA, Lindsten T, Thompson CB (July 1995)."CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL".Immunity.3(1): 87–98.doi:10.1016/1074-7613(95)90161-2.PMID7621080.
  20. ^Kovalev GI, Franklin DS, Coffield VM, Xiong Y, Su L (September 2001)."An important role of CDK inhibitor p18(INK4c) in modulating antigen receptor-mediated T cell proliferation".Journal of Immunology.167(6): 3285–92.doi:10.4049/jimmunol.167.6.3285.PMC4435948.PMID11544316.
  21. ^Orabona C, Grohmann U, Belladonna ML, Fallarino F, Vacca C, Bianchi R, et al. (November 2004). "CD28 induces immunostimulatory signals in dendritic cells via CD80 and CD86".Nature Immunology.5(11): 1134–42.doi:10.1038/ni1124.PMID15467723.S2CID6080497.
  22. ^abcNolan A, Kobayashi H, Naveed B, Kelly A, Hoshino Y, Hoshino S, et al. (August 2009)."Differential role for CD80 and CD86 in the regulation of the innate immune response in murine polymicrobial sepsis".PLOS ONE.4(8): e6600.Bibcode:2009PLoSO...4.6600N.doi:10.1371/journal.pone.0006600.PMC2719911.PMID19672303.
  23. ^abChambers BJ, Salcedo M, Ljunggren HG (October 1996)."Triggering of natural killer cells by the costimulatory molecule CD80 (B7-1)".Immunity.5(4): 311–7.doi:10.1016/S1074-7613(00)80257-5.PMID8885864.
  24. ^Sabzevari H, Kantor J, Jaigirdar A, Tagaya Y, Naramura M, Hodge J, Bernon J, Schlom J (February 2001)."Acquisition of CD80 (B7-1) by T cells".Journal of Immunology.166(4): 2505–13.doi:10.4049/jimmunol.166.4.2505.PMID11160311.
  25. ^Rau FC, Dieter J, Luo Z, Priest SO, Baumgarth N (December 2009)."B7-1/2 (CD80/CD86) direct signaling to B cells enhances IgG secretion".Journal of Immunology.183(12): 7661–71.doi:10.4049/jimmunol.0803783.PMC2795108.PMID19933871.
  26. ^Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ (July 2007)."Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses".Immunity.27(1): 111–22.doi:10.1016/j.immuni.2007.05.016.PMC2707944.PMID17629517.
  27. ^Windhagen A, Newcombe J, Dangond F, Strand C, Woodroofe MN, Cuzner ML, Hafler DA (December 1995)."Expression of costimulatory molecules B7-1 (CD80), B7-2 (CD86), and interleukin 12 cytokine in multiple sclerosis lesions".The Journal of Experimental Medicine.182(6): 1985–96.doi:10.1084/jem.182.6.1985.PMC2192240.PMID7500044.
  28. ^Wong CK, Lit LC, Tam LS, Li EK, Lam CW (August 2005)."Aberrant production of soluble costimulatory molecules CTLA-4, CD28, CD80 and CD86 in patients with systemic lupus erythematosus".Rheumatology.44(8). Oxford, England: 989–94.doi:10.1093/rheumatology/keh663.PMID15870153.
  29. ^Nolan A, Weiden M, Kelly A, Hoshino Y, Hoshino S, Mehta N, Gold JA (February 2008)."CD40 and CD80/86 act synergistically to regulate inflammation and mortality in polymicrobial sepsis".American Journal of Respiratory and Critical Care Medicine.177(3): 301–8.doi:10.1164/rccm.200703-515OC.PMC2218847.PMID17989345.
  30. ^Pinchuk LM, Polacino PS, Agy MB, Klaus SJ, Clark EA (July 1994). "The role of CD40 and CD80 accessory cell molecules in dendritic cell-dependent HIV-1 infection".Immunity.1(4): 317–25.doi:10.1016/1074-7613(94)90083-3.PMID7534204.
  31. ^Yang R, Cai Z, Zhang Y, Yutzy WH, Roby KF, Roden RB (July 2006)."CD80 in immune suppression by mouse ovarian carcinoma-associated Gr-1+CD11b+ myeloid cells".Cancer Research.66(13): 6807–15.doi:10.1158/0008-5472.CAN-05-3755.PMID16818658.
  32. ^Imasuen I, Bozeman E, He S, Patel J, Selvaraj P (May 2013)."Increased B7-1 (CD80) expression reduces overall tumorigenicity and metastatic potential of the murine pancreatic cancer cell model Pan02 (P2085)".The Journal of Immunology.190(1 Supplement): 53.43.doi:10.4049/jimmunol.190.Supp.53.43.S2CID82772085.
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