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This article is about the molecule. For the compilation album, see CD86 (album).
CD86
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCD86, B7-2, B7.2, B70, CD28LG2, LAB72, CD86 molecule
External IDsOMIM: 601020 MGI: 101773 HomoloGene: 10443 GeneCards: CD86
Orthologs
SpeciesHumanMouse
Entrez

942

12524

Ensembl

ENSG00000114013

ENSMUSG00000022901

UniProt

P42081

P42082

RefSeq (mRNA)

NM_176892
NM_001206924
NM_001206925
NM_006889
NM_175862

NM_019388

RefSeq (protein)

NP_001193853
NP_001193854
NP_008820
NP_787058
NP_795711

NP_062261

Location (UCSC)Chr 3: 122.06 – 122.12 MbChr 16: 36.42 – 36.49 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Cluster of Differentiation 86 (also known as CD86 and B7-2) is a protein constitutively expressed on dendritic cells, Langerhans cells, macrophages, B-cells (including memory B-cells), and on other antigen-presenting cells.[5] Along with CD80, CD86 provides costimulatory signals necessary for T cell activation and survival. Depending on the ligand bound, CD86 can signal for self-regulation and cell-cell association, or for attenuation of regulation and cell-cell disassociation.[6]

The CD86 gene encodes a type I membrane protein that is a member of the immunoglobulin superfamily.[7] Alternative splicing results in two transcript variants encoding different isoforms. Additional transcript variants have been described, but their full-length sequences have not been determined.[8]

Structure[edit]

CD86 belongs to the B7 family of the immunoglobulin superfamily.[9] It is a 70 kDa glycoprotein made up of 329 amino acids. Both CD80 and CD86 share a conserved amino acid motif that forms their ligand binding domain.[10] CD86 consists of Ig-like extracellular domains (one variable and one constant), a transmembrane region and a short cytoplasmic domain that is longer than that of CD80.[11][12] costimulatory ligands CD80 and CD86 can be found on professional antigen presenting cells such as monocytes, dendritic cells, and even activated B-cells. They can also be induced on other cell types, for example T cells.[13] CD86 expression is more abundant compared to CD80, and upon its activation is CD86 increased faster than CD80.[14]

At the protein level, CD86 shares 25% identity with CD80[15] and both are coded on human chromosome 3q13.33q21.[16]

Role in co-stimulation, T-cell activation and inhibition[edit]

CD86 and CD80 bind as ligands to costimulatory molecule CD28 on the surface of all naïve T cells,[17] and to the inhibitory receptor CTLA-4 (cytotoxic T-lymphocyte antigen-4, also known as CD152).[18][19] CD28 and CTLA-4 have important, but opposite roles in the stimulation of T cells. Binding to CD28 promotes T cell responses, while binding to CTLA-4 inhibits them.[20]

The interaction between CD86 (CD80) expressed on the surface of an antigen-presenting cell with CD28 on the surface of a mature, naive T-cell, is required for T-cell activation.[21] To become activated, lymphocyte must engage both antigen and costimulatory ligand on the same antigen-presenting cell. T cell receptor (TCR) interacts with major histocompatibility complex (MHC) class II molecules,[13] and this signalization must be accompanied by costimulatory signals, provided by a costimulatory ligand. These costimulatory signals are necessary to prevent anergy and are provided by the interaction between CD80/CD86 and CD28 costimulatory molecule.[22][23]

This protein interaction is also essential for T lymphocytes to receive the full activation signal, which in turn leads to T cell differentiation and division, production of interleukin 2 and clonal expansion.[9][22] Interaction between CD86 and CD28 activates mitogen-activated protein kinase and transcription factor nf-κB in the T-cell. These proteins up-regulate production of CD40L (used in B-cell activation), IL-21 and IL-21R (used for division/proliferation), and IL-2, among other cytokines.[21] The interaction also regulates self-tolerance by supporting the homeostatis of CD4+CD25+ Tregulatory cell, also known as Tregs.[9]

CTLA-4 is a coinhibitory molecule that is induced on activated T cells. Interaction between CTLA-4 and CD80/CD86 leads to delivery of negative signals into T cells and reduction of number of costimulatory molecules on the cell surface. It can also trigger a signaling pathway responsible for expression of enzyme IDO (indolamine-2,3-dioxygenase). This enzyme can metabolize amino acid tryptophan, which is an important component for successful proliferation and differentiation of T lymphocytes. IDO reduces the concentration of tryptophan in the environment, thereby suppressing the activation of conventional T cells, while also promoting the function of regulatory T cells.[24][25]

Both CD80 and CD86 bind CTLA-4 with higher affinity than CD28. This allows CTLA-4 to outcompete CD28 for CD80/CD86 binding.[23][26] Between CD80 and CD86, CD80 appears to have a higher affinity for both CTLA-4 and CD28 than CD86. This suggest that CD80 is more potent ligand than CD86,[15] but studies using CD80 and CD86 knockout mice have shown that CD86 is more important in T cell activation than CD80.[27]

Treg mediation[edit]

Can't load image
CTLA-4 inhibits CD86 - CD28 binding when active on Tregulatory cells

Pathways in the B7:CD28 family have key roles in the regulation of T cell activation and tolerance. Their negative second signals are responsible for downregulation of cell responses. For all these reasons are these pathways considered as therapeutic targets.[9]

Regulatory T cells produce CTLA-4. Due to its interaction with CD80/CD86, Tregs can compete with conventional T cells and block their costimulatory signals. Treg expression of CTLA-4 can effectively downregulate both CD80 and CD86 on APCs,[28] suppress the immune response and lead to increased anergy.[6] Since CTLA-4 binds to CD86 with higher affinity than CD28, the co-stimulation necessary for proper T-cell activation is also affected.[29] It was shown in a work from Sagurachi group that Treg cells were able to downregulate CD80 and CD86, but not CD40 or MHC class II on DC in a way that was adhesion dependent. Downregulation was blocked by anti-CTLA-4 antibody and was cancelled if Treg cells were CTLA-4 deficient.[30]

When bound to CTLA-4, CD86 can be removed from the surface of an APC and onto the Treg cell in a process called trogocytosis.[6] Blocking this process with anti-CTLA-4 antibodies is useful for a specific type of cancer immunotherapy called "Cancer therapy by inhibition of negative immune regulation".[31] Japanese immunologist Tasuku Honjo and American immunologist James P. Allison won the Nobel Prize in Physiology or Medicine in 2018 for their work on this topic.

Role in pathology[edit]

Roles of both CD80 and CD86 are studied in context of many pathologies. Selective inhibition of costimulatory inhibitors was examined in a model of allergic pulmonary inflammation and airway hyper-responsiveness (AHR).[32] Since initial host response to Staphylococcus aureus, especially the immune response based on T cells, is a contributing factor in the pathogenesis of acute pneumonia, role of the CD80/CD86 pathway in pathogenesis was investigated.[33] The costimulatory molecules were also investigated in context of Bronchial Astma,[34] Treg in cancer,[35] and immunotherapy.[36]

See also[edit]

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000114013 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022901 – 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. ^ Lenschow DJ, Su GH, Zuckerman LA, Nabavi N, Jellis CL, Gray GS, et al. (December 1993). "Expression and functional significance of an additional ligand for CTLA-4". Proceedings of the National Academy of Sciences of the United States of America. 90 (23): 11054–8. Bibcode:1993PNAS...9011054L. doi:10.1073/pnas.90.23.11054. PMC 47920. PMID 7504292.
  6. ^ a b c Ohue Y, Nishikawa H (July 2019). "Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target?". Cancer Science. 110 (7): 2080–2089. doi:10.1111/cas.14069. PMC 6609813. PMID 31102428.
  7. ^ Chen C, Gault A, Shen L, Nabavi N (May 1994). "Molecular cloning and expression of early T cell costimulatory molecule-1 and its characterization as B7-2 molecule". Journal of Immunology. 152 (10): 4929–36. doi:10.4049/jimmunol.152.10.4929. PMID 7513726. S2CID 22260156.
  8. ^ "Entrez Gene: CD86 CD86 molecule".
  9. ^ a b c d Greenwald RJ, Freeman GJ, Sharpe AH (2005). "The B7 family revisited". Annual Review of Immunology. 23: 515–48. doi:10.1146/annurev.immunol.23.021704.115611. PMID 15771580.
  10. ^ Yu C, Sonnen AF, George R, Dessailly BH, Stagg LJ, Evans EJ, et al. (February 2011). "Rigid-body ligand recognition drives cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor triggering". The Journal of Biological Chemistry. 286 (8): 6685–96. doi:10.1074/jbc.M110.182394. PMC 3057841. PMID 21156796.
  11. ^ Freeman GJ, Borriello F, Hodes RJ, Reiser H, Hathcock KS, Laszlo G, et al. (November 1993). "Uncovering of functional alternative CTLA-4 counter-receptor in B7-deficient mice". Science. 262 (5135): 907–9. Bibcode:1993Sci...262..907F. doi:10.1126/science.7694362. PMID 7694362.
  12. ^ Sharpe AH, Freeman GJ (February 2002). "The B7-CD28 superfamily". Nature Reviews. Immunology. 2 (2): 116–26. doi:10.1038/nri727. PMID 11910893. S2CID 205492817.
  13. ^ a b Murphy K, Weaver C, Janeway C (2017). Janeway's immunobiology (9th ed.). New York. ISBN 978-0-8153-4505-3. OCLC 933586700.{{cite book}}: CS1 maint: location missing publisher (link)
  14. ^ Sansom DM (October 2000). "CD28, CTLA-4 and their ligands: who does what and to whom?". Immunology. 101 (2): 169–77. doi:10.1046/j.1365-2567.2000.00121.x. PMC 2327073. PMID 11012769.
  15. ^ a b Collins AV, Brodie DW, Gilbert RJ, Iaboni A, Manso-Sancho R, Walse B, et al. (August 2002). "The interaction properties of costimulatory molecules revisited". Immunity. 17 (2): 201–10. doi:10.1016/s1074-7613(02)00362-x. PMID 12196291.
  16. ^ Mir MA (25 May 2015). Developing costimulatory molecules for immunotherapy of diseases. London. ISBN 978-0-12-802675-5. OCLC 910324332.{{cite book}}: CS1 maint: location missing publisher (link)
  17. ^ Linsley PS, Brady W, Grosmaire L, Aruffo A, Damle NK, Ledbetter JA (March 1991). "Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation". The Journal of Experimental Medicine. 173 (3): 721–30. doi:10.1084/jem.173.3.721. PMC 2118836. PMID 1847722.
  18. ^ Lim TS, Goh JK, Mortellaro A, Lim CT, Hämmerling GJ, Ricciardi-Castagnoli P (2012). "CD80 and CD86 differentially regulate mechanical interactions of T-cells with antigen-presenting dendritic cells and B-cells". PLOS ONE. 7 (9): e45185. Bibcode:2012PLoSO...745185L. doi:10.1371/journal.pone.0045185. PMC 3443229. PMID 23024807.
  19. ^ Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA (September 1991). "CTLA-4 is a second receptor for the B cell activation antigen B7". The Journal of Experimental Medicine. 174 (3): 561–9. doi:10.1084/jem.174.3.561. PMC 2118936. PMID 1714933.
  20. ^ Sansom DM, Manzotti CN, Zheng Y (June 2003). "What's the difference between CD80 and CD86?". Trends in Immunology. 24 (6): 314–9. doi:10.1016/s1471-4906(03)00111-x. PMID 12810107.
  21. ^ a b Dyck L, Mills KH (May 2017). "Immune checkpoints and their inhibition in cancer and infectious diseases". European Journal of Immunology. 47 (5): 765–779. doi:10.1002/eji.201646875. PMID 28393361.
  22. ^ a b Coyle AJ, Gutierrez-Ramos JC (March 2001). "The expanding B7 superfamily: increasing complexity in costimulatory signals regulating T cell function". Nature Immunology. 2 (3): 203–9. doi:10.1038/85251. PMID 11224518. S2CID 20542148.
  23. ^ a b Gause WC, Urban JF, Linsley P, Lu P (1995). "Role of B7 signaling in the differentiation of naive CD4+ T cells to effector interleukin-4-producing T helper cells". Immunologic Research. 14 (3): 176–88. doi:10.1007/BF02918215. PMID 8778208. S2CID 20098311.
  24. ^ Chen L, Flies DB (April 2013). "Molecular mechanisms of T cell co-stimulation and co-inhibition". Nature Reviews. Immunology. 13 (4): 227–42. doi:10.1038/nri3405. PMC 3786574. PMID 23470321.
  25. ^ Munn DH, Sharma MD, Mellor AL (April 2004). "Ligation of B7-1/B7-2 by human CD4+ T cells triggers indoleamine 2,3-dioxygenase activity in dendritic cells". Journal of Immunology. 172 (7): 4100–10. doi:10.4049/jimmunol.172.7.4100. PMID 15034022.
  26. ^ Walker LS, Sansom DM (November 2011). "The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses". Nature Reviews. Immunology. 11 (12): 852–63. doi:10.1038/nri3108. PMID 22116087. S2CID 9617595.
  27. ^ Borriello F, Sethna MP, Boyd SD, Schweitzer AN, Tivol EA, Jacoby D, et al. (March 1997). "B7-1 and B7-2 have overlapping, critical roles in immunoglobulin class switching and germinal center formation". Immunity. 6 (3): 303–13. doi:10.1016/s1074-7613(00)80333-7. PMID 9075931.
  28. ^ Walker LS, Sansom DM (February 2015). "Confusing signals: recent progress in CTLA-4 biology". Trends in Immunology. 36 (2): 63–70. doi:10.1016/j.it.2014.12.001. PMC 4323153. PMID 25582039.
  29. ^ Lightman SM, Utley A, Lee KP (2019-05-03). "Survival of Long-Lived Plasma Cells (LLPC): Piecing Together the Puzzle". Frontiers in Immunology. 10: 965. doi:10.3389/fimmu.2019.00965. PMC 6510054. PMID 31130955.
  30. ^ Onishi Y, Fehervari Z, Yamaguchi T, Sakaguchi S (July 2008). "Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation". Proceedings of the National Academy of Sciences of the United States of America. 105 (29): 10113–8. Bibcode:2008PNAS..10510113O. doi:10.1073/pnas.0711106105. PMC 2481354. PMID 18635688.
  31. ^ Chen R, Ganesan A, Okoye I, Arutyunova E, Elahi S, Lemieux MJ, et al. (March 2020). "Targeting B7-1 in immunotherapy". Medicinal Research Reviews. 40 (2): 654–682. doi:10.1002/med.21632. PMID 31448437. S2CID 201748060.
  32. ^ Mark DA, Donovan CE, De Sanctis GT, Krinzman SJ, Kobzik L, Linsley PS, et al. (November 1998). "Both CD80 and CD86 co-stimulatory molecules regulate allergic pulmonary inflammation". International Immunology. 10 (11): 1647–55. doi:10.1093/intimm/10.11.1647. PMID 9846693.
  33. ^ Parker D (July 2018). "CD80/CD86 signaling contributes to the proinflammatory response of Staphylococcus aureus in the airway". Cytokine. 107: 130–136. doi:10.1016/j.cyto.2018.01.016. PMC 5916031. PMID 29402722.
  34. ^ Chen YQ, Shi HZ (January 2006). "CD28/CTLA-4--CD80/CD86 and ICOS--B7RP-1 costimulatory pathway in bronchial asthma". Allergy. 61 (1): 15–26. doi:10.1111/j.1398-9995.2006.01008.x. PMID 16364152. S2CID 23564785.
  35. ^ Ohue Y, Nishikawa H (July 2019). "Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target?". Cancer Science. 110 (7): 2080–2089. doi:10.1111/cas.14069. PMC 6609813. PMID 31102428.
  36. ^ Bourque J, Hawiger D (2018). "Immunomodulatory Bonds of the Partnership between Dendritic Cells and T Cells". Critical Reviews in Immunology. 38 (5): 379–401. doi:10.1615/CritRevImmunol.2018026790. PMC 6380512. PMID 30792568.

External links[edit]

Further reading[edit]

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

source: https://en.wikipedia.org/wiki/CD86

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