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CD86
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1I85, 1NCN
Identifiers
Aliases	CD86, B7-2, B7.2, B70, CD28LG2, LAB72, CD86 molecule
External IDs	OMIM: 601020; MGI: 101773; HomoloGene: 10443; GeneCards: CD86; OMA:CD86 - orthologs
Gene location (Human) Chr. Chromosome 3 (human) Band 3q13.33 Start 122,055,362 bp End 122,121,139 bp
Gene location (Mouse) Chr. Chromosome 16 (mouse) Band 16 B3|16 25.72 cM Start 36,424,231 bp End 36,486,443 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte granulocyte appendix testicle blood lymph node gallbladder spleen right lung rectum Top expressed in spleen lumbar spinal ganglion granulocyte mesenteric lymph nodes thymus stroma of bone marrow blood subcutaneous adipose tissue Paneth cell lumbar subsegment of spinal cord More reference expression data BioGPS More reference expression data
Gene ontology Molecular function coreceptor activity virus receptor activity protein binding signaling receptor binding phosphatidylinositol-4,5-bisphosphate 3-kinase activity signaling receptor activity Cellular component integral component of membrane intracellular membrane-bounded organelle membrane plasma membrane cell surface extracellular exosome external side of plasma membrane Biological process response to yeast adaptive immune response response to interferon-gamma immune system process cell-cell signaling T cell costimulation ageing myeloid dendritic cell differentiation cellular response to cytokine stimulus T cell proliferation involved in immune response toll-like receptor signaling pathway positive regulation of transcription, DNA-templated B cell activation response to lipopolysaccharide cellular response to metal ion negative regulation of T cell anergy defense response to virus immune response positive regulation of T cell proliferation positive regulation of cell population proliferation positive regulation of T-helper 2 cell differentiation viral entry into host cell viral process toll-like receptor 3 signaling pathway cellular response to lipopolysaccharide T cell activation positive regulation of activated T cell proliferation phosphatidylinositol phosphate biosynthetic process positive regulation of protein kinase B signaling signal transduction cell surface receptor signaling pathway cytokine-mediated signaling pathway negative regulation of T cell proliferation Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr 16: 36.42 – 36.49 Mb PubMed search
Wikidata
View/Edit Human View/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. 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.

The CD86 gene encodes a type I membrane protein that is a member of the immunoglobulin superfamily. 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.

Structure

CD86 belongs to the B7 family of the immunoglobulin superfamily. 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. 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. 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. CD86 expression is more abundant compared to CD80, and upon its activation is CD86 increased faster than CD80.

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

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, and to the inhibitory receptor CTLA-4 (cytotoxic T-lymphocyte antigen-4, also known as CD152). 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.

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. 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, 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.

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. 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.

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.

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

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.

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, 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. 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.

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". 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). 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. The costimulatory molecules were also investigated in context of Bronchial Astma, Treg in cancer, and immunotherapy.

See also

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

References

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External links

• Human CD86 genome location and CD86 gene details page in the UCSC Genome Browser.

Further reading

• Davila S, Froeling FE, Tan A, Bonnard C, Boland GJ, Snippe H, et al. (April 2010). "New genetic associations detected in a host response study to hepatitis B vaccine". Genes and Immunity. 11 (3): 232–8. doi:10.1038/gene.2010.1. PMID 20237496.
• Csillag A, Boldogh I, Pazmandi K, Magyarics Z, Gogolak P, Sur S, et al. (March 2010). "Pollen-induced oxidative stress influences both innate and adaptive immune responses via altering dendritic cell functions". Journal of Immunology. 184 (5): 2377–85. doi:10.4049/jimmunol.0803938. PMC 3028537. PMID 20118277.
• Bossé Y, Lemire M, Poon AH, Daley D, He JQ, Sandford A, et al. (October 2009). "Asthma and genes encoding components of the vitamin D pathway". Respiratory Research. 10 (1): 98. doi:10.1186/1465-9921-10-98. PMC 2779188. PMID 19852851.
• Mosbruger TL, Duggal P, Goedert JJ, Kirk GD, Hoots WK, Tobler LH, et al. (May 2010). "Large-scale candidate gene analysis of spontaneous clearance of hepatitis C virus". The Journal of Infectious Diseases. 201 (9): 1371–80. doi:10.1086/651606. PMC 2853721. PMID 20331378.
• Bugeon L, Dallman MJ (October 2000). "Costimulation of T cells". American Journal of Respiratory and Critical Care Medicine. 162 (4 Pt 2): S164-8. doi:10.1164/ajrccm.162.supplement_3.15tac5. PMID 11029388.
• Pan XM, Gao LB, Liang WB, Liu Y, Zhu Y, Tang M, et al. (July 2010). "CD86 +1057 G/A polymorphism and the risk of colorectal cancer". DNA and Cell Biology. 29 (7): 381–6. doi:10.1089/dna.2009.1003. PMID 20380573.
• Dalla-Costa R, Pincerati MR, Beltrame MH, Malheiros D, Petzl-Erler ML (August 2010). "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. doi:10.1016/j.humimm.2010.04.001. PMID 20433886.
• Talmud PJ, Drenos F, Shah S, Shah T, Palmen J, Verzilli C, et al. (November 2009). "Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip". American Journal of Human Genetics. 85 (5): 628–42. doi:10.1016/j.ajhg.2009.10.014. PMC 2775832. PMID 19913121.
• Carreño LJ, Pacheco R, Gutierrez MA, Jacobelli S, Kalergis AM (November 2009). "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. doi:10.1111/j.1365-2567.2009.03138.x. PMC 2770681. PMID 20067533.
• Koyasu S (April 2003). "The role of PI3K in immune cells". Nature Immunology. 4 (4): 313–9. doi:10.1038/ni0403-313. PMID 12660731. S2CID 9951653.
• Kim SH, Lee JE, Kim SH, Jee YK, Kim YK, Park HS, et al. (December 2009). "Allelic variants of CD40 and CD40L genes interact to promote antibiotic-induced cutaneous allergic reactions". Clinical and Experimental Allergy. 39 (12): 1852–6. doi:10.1111/j.1365-2222.2009.03336.x. PMID 19735272. S2CID 26024387.
• Liu Y, Liang WB, Gao LB, Pan XM, Chen TY, Wang YY, et al. (November 2010). "CTLA4 and CD86 gene polymorphisms and susceptibility to chronic obstructive pulmonary disease". Human Immunology. 71 (11): 1141–6. doi:10.1016/j.humimm.2010.08.007. PMID 20732370.
• Ma XN, Wang X, Yan YY, Yang L, Zhang DL, Sheng X, et al. (June 2010). "Absence of association between CD86 +1057G/A polymorphism and coronary artery disease". DNA and Cell Biology. 29 (6): 325–8. doi:10.1089/dna.2009.0987. PMID 20230296.
• Ishizaki Y, Yukaya N, Kusuhara K, Kira R, Torisu H, Ihara K, et al. (April 2010). "PD1 as a common candidate susceptibility gene of subacute sclerosing panencephalitis". Human Genetics. 127 (4): 411–9. doi:10.1007/s00439-009-0781-z. PMID 20066438. S2CID 12633836.
• Chang TT, Kuchroo VK, Sharpe AH (2002). "Role of the B7-CD28/CTLA-4 pathway in autoimmune disease". Current Directions in Autoimmunity. 5: 113–30. doi:10.1159/000060550. ISBN 3-8055-7308-1. PMID 11826754.
• Grujic M, Bartholdy C, Remy M, Pinschewer DD, Christensen JP, Thomsen AR (August 2010). "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. doi:10.4049/jimmunol.0903894. PMID 20601595.
• Quaranta MG, Mattioli B, Giordani L, Viora M (November 2006). "The immunoregulatory effects of HIV-1 Nef on dendritic cells and the pathogenesis of AIDS". FASEB Journal. 20 (13): 2198–208. doi:10.1096/fj.06-6260rev. PMID 17077296. S2CID 3111709.
• Schuurhof A, Bont L, Siezen CL, Hodemaekers H, van Houwelingen HC, Kimman TG, et al. (June 2010). "Interleukin-9 polymorphism in infants with respiratory syncytial virus infection: an opposite effect in boys and girls". Pediatric Pulmonology. 45 (6): 608–13. doi:10.1002/ppul.21229. PMID 20503287. S2CID 24678182.
• Bailey SD, Xie C, Do R, Montpetit A, Diaz R, Mohan V, et al. (October 2010). "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. doi:10.2337/dc10-0452. PMC 2945168. PMID 20628086.
• Radziewicz H, Ibegbu CC, Hon H, Bédard N, Bruneau J, Workowski KA, et al. (March 2010). "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. doi:10.4049/jimmunol.0902994. PMC 2924663. PMID 20100932.

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

• Genes on human chromosome 3
• Clusters of differentiation