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]

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; OMA:CD86 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
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

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

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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

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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

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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

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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

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000114013Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022901Ensembl, May 2017
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  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.
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  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.
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  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.
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  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.
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Further reading

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