CD86 explained

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.^[1] 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.^[2]

The CD86 gene encodes a type I membrane protein that is a member of the immunoglobulin superfamily.^[3] 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.^[4]

Structure

CD86 belongs to the B7 family of the immunoglobulin superfamily.^[5] 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.^[6] 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.^{[7] [8]} 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.^[9] CD86 expression is more abundant compared to CD80, and upon its activation is CD86 increased faster than CD80.^[10]

At the protein level, CD86 shares 25% identity with CD80^[11] and both are coded on human chromosome 3q13.33q21.^[12]

Role in co-stimulation, T-cell activation and inhibition

CD86 and CD80 bind as ligands to costimulatory molecule CD28 on the surface of all naïve T cells,^[13] and to the inhibitory receptor CTLA-4 (cytotoxic T-lymphocyte antigen-4, also known as CD152).^{[14] [15]} 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.^[16]

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.^[17] 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,^[9] 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.^{[18] [19]}

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.^{[5] [18]} 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. The interaction also regulates self-tolerance by supporting the homeostatis of CD4+CD25+ Tregulatory cell, also known as Tregs.^[5]

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.^{[20] [21]}

Both CD80 and CD86 bind CTLA-4 with higher affinity than CD28. This allows CTLA-4 to outcompete CD28 for CD80/CD86 binding.^[22] 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,^[11] but studies using CD80 and CD86 knockout mice have shown that CD86 is more important in T cell activation than CD80.^[23]

Treg mediation

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.^[5]

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,^[24] suppress the immune response and lead to increased anergy. Since CTLA-4 binds to CD86 with higher affinity than CD28, the co-stimulation necessary for proper T-cell activation is also affected.^[25] 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.^[26]

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. 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".^[27] 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

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).^[28] 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.^[29] The costimulatory molecules were also investigated in context of Bronchial Astma,^[30] Treg in cancer,^[31] and immunotherapy.^[32]

See also

• Cluster of differentiation
• CD80
• CD28
• CTLA-4
• List of human clusters of differentiation for a list of CD molecules

References

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

Further reading

• Davila S, Froeling FE, Tan A, Bonnard C, Boland GJ, Snippe H, Hibberd ML, Seielstad M . New genetic associations detected in a host response study to hepatitis B vaccine . Genes and Immunity . 11 . 3 . 232–8 . April 2010 . 20237496 . 10.1038/gene.2010.1 . free .
• Csillag A, Boldogh I, Pazmandi K, Magyarics Z, Gogolak P, Sur S, Rajnavolgyi E, Bacsi A . Pollen-induced oxidative stress influences both innate and adaptive immune responses via altering dendritic cell functions . Journal of Immunology . 184 . 5 . 2377–85 . March 2010 . 20118277 . 3028537 . 10.4049/jimmunol.0803938 .
• Bossé Y, Lemire M, Poon AH, Daley D, He JQ, Sandford A, White JH, James AL, Musk AW, Palmer LJ, Raby BA, Weiss ST, Kozyrskyj AL, Becker A, Hudson TJ, Laprise C . Asthma and genes encoding components of the vitamin D pathway . Respiratory Research . 10 . 98 . October 2009 . 1 . 19852851 . 2779188 . 10.1186/1465-9921-10-98 . free .
• Mosbruger TL, Duggal P, Goedert JJ, Kirk GD, Hoots WK, Tobler LH, Busch M, Peters MG, Rosen HR, Thomas DL, Thio CL . Large-scale candidate gene analysis of spontaneous clearance of hepatitis C virus . The Journal of Infectious Diseases . 201 . 9 . 1371–80 . May 2010 . 20331378 . 2853721 . 10.1086/651606 .
• Bugeon L, Dallman MJ . Costimulation of T cells . American Journal of Respiratory and Critical Care Medicine . 162 . 4 Pt 2 . S164-8 . October 2000 . 11029388 . 10.1164/ajrccm.162.supplement_3.15tac5 .
• Pan XM, Gao LB, Liang WB, Liu Y, Zhu Y, Tang M, Li YB, Zhang L . CD86 +1057 G/A polymorphism and the risk of colorectal cancer . DNA and Cell Biology . 29 . 7 . 381–6 . July 2010 . 20380573 . 10.1089/dna.2009.1003 .
• Dalla-Costa R, Pincerati MR, Beltrame MH, Malheiros D, Petzl-Erler ML . Polymorphisms in the 2q33 and 3q21 chromosome regions including T-cell coreceptor and ligand genes may influence susceptibility to pemphigus foliaceus . Human Immunology . 71 . 8 . 809–17 . August 2010 . 20433886 . 10.1016/j.humimm.2010.04.001 .
• Talmud PJ, Drenos F, Shah S, Shah T, Palmen J, Verzilli C, Gaunt TR, Pallas J, Lovering R, Li K, Casas JP, Sofat R, Kumari M, Rodriguez S, Johnson T, Newhouse SJ, Dominiczak A, Samani NJ, Caulfield M, Sever P, Stanton A, Shields DC, Padmanabhan S, Melander O, Hastie C, Delles C, Ebrahim S, Marmot MG, Smith GD, Lawlor DA, Munroe PB, Day IN, Kivimaki M, Whittaker J, Humphries SE, Hingorani AD . Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip . American Journal of Human Genetics . 85 . 5 . 628–42 . November 2009 . 19913121 . 2775832 . 10.1016/j.ajhg.2009.10.014 .
• Carreño LJ, Pacheco R, Gutierrez MA, Jacobelli S, Kalergis AM . Disease activity in systemic lupus erythematosus is associated with an altered expression of low-affinity Fc gamma receptors and costimulatory molecules on dendritic cells . Immunology . 128 . 3 . 334–41 . November 2009 . 20067533 . 2770681 . 10.1111/j.1365-2567.2009.03138.x .
• Koyasu S . The role of PI3K in immune cells . Nature Immunology . 4 . 4 . 313–9 . April 2003 . 12660731 . 10.1038/ni0403-313 . 9951653 .
• Kim SH, Lee JE, Kim SH, Jee YK, Kim YK, Park HS, Min KU, Park HW . Allelic variants of CD40 and CD40L genes interact to promote antibiotic-induced cutaneous allergic reactions . Clinical and Experimental Allergy . 39 . 12 . 1852–6 . December 2009 . 19735272 . 10.1111/j.1365-2222.2009.03336.x . 26024387 .
• Liu Y, Liang WB, Gao LB, Pan XM, Chen TY, Wang YY, Xue H, Zhang LS, Zhang L . CTLA4 and CD86 gene polymorphisms and susceptibility to chronic obstructive pulmonary disease . Human Immunology . 71 . 11 . 1141–6 . November 2010 . 20732370 . 10.1016/j.humimm.2010.08.007 .
• Ma XN, Wang X, Yan YY, Yang L, Zhang DL, Sheng X, Liu XM, Huang H, Dai J, Zhong YJ, Liao LC . Absence of association between CD86 +1057G/A polymorphism and coronary artery disease . DNA and Cell Biology . 29 . 6 . 325–8 . June 2010 . 20230296 . 10.1089/dna.2009.0987 .
• Ishizaki Y, Yukaya N, Kusuhara K, Kira R, Torisu H, Ihara K, Sakai Y, Sanefuji M, Pipo-Deveza JR, Silao CL, Sanchez BC, Lukban MB, Salonga AM, Hara T . PD1 as a common candidate susceptibility gene of subacute sclerosing panencephalitis . Human Genetics . 127 . 4 . 411–9 . April 2010 . 20066438 . 10.1007/s00439-009-0781-z . 12633836 .
• Chang TT, Kuchroo VK, Sharpe AH . Role of the B7-CD28/CTLA-4 pathway in autoimmune disease . Current Directions in Autoimmunity . 5 . 113–30 . 2002 . 11826754 . 10.1159/000060550 . 3-8055-7308-1 .
• Grujic M, Bartholdy C, Remy M, Pinschewer DD, Christensen JP, Thomsen AR . The role of CD80/CD86 in generation and maintenance of functional virus-specific CD8+ T cells in mice infected with lymphocytic choriomeningitis virus . Journal of Immunology . 185 . 3 . 1730–43 . August 2010 . 20601595 . 10.4049/jimmunol.0903894 . free .
• Quaranta MG, Mattioli B, Giordani L, Viora M . The immunoregulatory effects of HIV-1 Nef on dendritic cells and the pathogenesis of AIDS . FASEB Journal . 20 . 13 . 2198–208 . November 2006 . 17077296 . 10.1096/fj.06-6260rev . free . 3111709 .
• Schuurhof A, Bont L, Siezen CL, Hodemaekers H, van Houwelingen HC, Kimman TG, Hoebee B, Kimpen JL, Janssen R . Interleukin-9 polymorphism in infants with respiratory syncytial virus infection: an opposite effect in boys and girls . Pediatric Pulmonology . 45 . 6 . 608–13 . June 2010 . 20503287 . 10.1002/ppul.21229 . 24678182 .
• Bailey SD, Xie C, Do R, Montpetit A, Diaz R, Mohan V, Keavney B, Yusuf S, Gerstein HC, Engert JC, Anand S . Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study . Diabetes Care . 33 . 10 . 2250–3 . October 2010 . 20628086 . 2945168 . 10.2337/dc10-0452 .
• Radziewicz H, Ibegbu CC, Hon H, Bédard N, Bruneau J, Workowski KA, Knechtle SJ, Kirk AD, Larsen CP, Shoukry NH, Grakoui A . Transient CD86 expression on hepatitis C virus-specific CD8+ T cells in acute infection is linked to sufficient IL-2 signaling . Journal of Immunology . 184 . 5 . 2410–22 . March 2010 . 20100932 . 2924663 . 10.4049/jimmunol.0902994 .