CD86

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.{{cite journal | vauthors = Lenschow DJ, Su GH, Zuckerman LA, Nabavi N, Jellis CL, Gray GS, Miller J, Bluestone JA | title = Expression and functional significance of an additional ligand for CTLA-4 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 23 | pages = 11054–8 | date = December 1993 | pmid = 7504292 | pmc = 47920 | doi = 10.1073/pnas.90.23.11054 | bibcode = 1993PNAS...9011054L | doi-access = free }} 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.{{cite journal | vauthors = Ohue Y, Nishikawa H | title = Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target? | journal = Cancer Science | volume = 110 | issue = 7 | pages = 2080–2089 | date = July 2019 | pmid = 31102428 | pmc = 6609813 | doi = 10.1111/cas.14069 }}

The CD86 gene encodes a type I membrane protein that is a member of the immunoglobulin superfamily.{{cite journal | vauthors = Chen C, Gault A, Shen L, Nabavi N | title = Molecular cloning and expression of early T cell costimulatory molecule-1 and its characterization as B7-2 molecule | journal = Journal of Immunology | volume = 152 | issue = 10 | pages = 4929–36 | date = May 1994 | doi = 10.4049/jimmunol.152.10.4929 | pmid = 7513726 | s2cid = 22260156 | doi-access = free }} 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.{{cite web|url=https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=942|title=Entrez Gene: CD86 CD86 molecule}}

Structure

CD86 belongs to the B7 family of the immunoglobulin superfamily.{{cite journal | vauthors = Greenwald RJ, Freeman GJ, Sharpe AH | title = The B7 family revisited | journal = Annual Review of Immunology | volume = 23 | pages = 515–48 | date = 2005 | pmid = 15771580 | doi = 10.1146/annurev.immunol.23.021704.115611 }} 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.{{cite journal | vauthors = Yu C, Sonnen AF, George R, Dessailly BH, Stagg LJ, Evans EJ, Orengo CA, Stuart DI, Ladbury JE, Ikemizu S, Gilbert RJ, Davis SJ | title = Rigid-body ligand recognition drives cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor triggering | journal = The Journal of Biological Chemistry | volume = 286 | issue = 8 | pages = 6685–96 | date = February 2011 | pmid = 21156796 | pmc = 3057841 | doi = 10.1074/jbc.M110.182394 | doi-access = free }} 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.{{cite journal | vauthors = Freeman GJ, Borriello F, Hodes RJ, Reiser H, Hathcock KS, Laszlo G, McKnight AJ, Kim J, Du L, Lombard DB | title = Uncovering of functional alternative CTLA-4 counter-receptor in B7-deficient mice | journal = Science | volume = 262 | issue = 5135 | pages = 907–9 | date = November 1993 | pmid = 7694362 | doi = 10.1126/science.7694362 | bibcode = 1993Sci...262..907F }}{{cite journal | vauthors = Sharpe AH, Freeman GJ | title = The B7-CD28 superfamily | journal = Nature Reviews. Immunology | volume = 2 | issue = 2 | pages = 116–26 | date = February 2002 | pmid = 11910893 | doi = 10.1038/nri727 | s2cid = 205492817 }} 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.{{Cite book| vauthors = Murphy K, Weaver C, Janeway C |title=Janeway's immunobiology|year=2017|isbn=978-0-8153-4505-3|edition=9th|location=New York|oclc=933586700}} CD86 expression is more abundant compared to CD80, and upon its activation is CD86 increased faster than CD80.{{cite journal | vauthors = Sansom DM | title = CD28, CTLA-4 and their ligands: who does what and to whom? | journal = Immunology | volume = 101 | issue = 2 | pages = 169–77 | date = October 2000 | pmid = 11012769 | pmc = 2327073 | doi = 10.1046/j.1365-2567.2000.00121.x }}

At the protein level, CD86 shares 25% identity with CD80{{cite journal | vauthors = Collins AV, Brodie DW, Gilbert RJ, Iaboni A, Manso-Sancho R, Walse B, Stuart DI, van der Merwe PA, Davis SJ | title = The interaction properties of costimulatory molecules revisited | journal = Immunity | volume = 17 | issue = 2 | pages = 201–10 | date = August 2002 | pmid = 12196291 | doi = 10.1016/s1074-7613(02)00362-x | doi-access = free }} and both are coded on human chromosome 3q13.33q21.{{Cite book| vauthors = Mir MA |title=Developing costimulatory molecules for immunotherapy of diseases|date=25 May 2015|isbn=978-0-12-802675-5|location=London|oclc=910324332}}

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,{{cite journal | vauthors = Linsley PS, Brady W, Grosmaire L, Aruffo A, Damle NK, Ledbetter JA | title = Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation | journal = The Journal of Experimental Medicine | volume = 173 | issue = 3 | pages = 721–30 | date = March 1991 | pmid = 1847722 | pmc = 2118836 | doi = 10.1084/jem.173.3.721 }} and to the inhibitory receptor CTLA-4 (cytotoxic T-lymphocyte antigen-4, also known as CD152).{{cite journal | vauthors = Lim TS, Goh JK, Mortellaro A, Lim CT, Hämmerling GJ, Ricciardi-Castagnoli P | title = CD80 and CD86 differentially regulate mechanical interactions of T-cells with antigen-presenting dendritic cells and B-cells | journal = PLOS ONE | volume = 7 | issue = 9 | pages = e45185 | date = 2012 | pmid = 23024807 | pmc = 3443229 | doi = 10.1371/journal.pone.0045185 | bibcode = 2012PLoSO...745185L | doi-access = free }}{{cite journal | vauthors = Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA | title = CTLA-4 is a second receptor for the B cell activation antigen B7 | journal = The Journal of Experimental Medicine | volume = 174 | issue = 3 | pages = 561–9 | date = September 1991 | pmid = 1714933 | pmc = 2118936 | doi = 10.1084/jem.174.3.561 }} 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.{{cite journal | vauthors = Sansom DM, Manzotti CN, Zheng Y | title = What's the difference between CD80 and CD86? | journal = Trends in Immunology | volume = 24 | issue = 6 | pages = 314–9 | date = June 2003 | pmid = 12810107 | doi = 10.1016/s1471-4906(03)00111-x }}

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.{{cite journal | vauthors = Dyck L, Mills KH | title = Immune checkpoints and their inhibition in cancer and infectious diseases | journal = European Journal of Immunology | volume = 47 | issue = 5 | pages = 765–779 | date = May 2017 | pmid = 28393361 | doi = 10.1002/eji.201646875 | doi-access = free }} 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.{{cite journal | vauthors = Coyle AJ, Gutierrez-Ramos JC | title = The expanding B7 superfamily: increasing complexity in costimulatory signals regulating T cell function | journal = Nature Immunology | volume = 2 | issue = 3 | pages = 203–9 | date = March 2001 | pmid = 11224518 | doi = 10.1038/85251 | s2cid = 20542148 }}{{cite journal | vauthors = Gause WC, Urban JF, Linsley P, Lu P | title = Role of B7 signaling in the differentiation of naive CD4+ T cells to effector interleukin-4-producing T helper cells | journal = Immunologic Research | volume = 14 | issue = 3 | pages = 176–88 | date = 1995 | pmid = 8778208 | doi = 10.1007/BF02918215 | s2cid = 20098311 | doi-access = free }}

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.{{cite journal | vauthors = Chen L, Flies DB | title = Molecular mechanisms of T cell co-stimulation and co-inhibition | journal = Nature Reviews. Immunology | volume = 13 | issue = 4 | pages = 227–42 | date = April 2013 | pmid = 23470321 | pmc = 3786574 | doi = 10.1038/nri3405 }}{{cite journal | vauthors = Munn DH, Sharma MD, Mellor AL | title = Ligation of B7-1/B7-2 by human CD4+ T cells triggers indoleamine 2,3-dioxygenase activity in dendritic cells | journal = Journal of Immunology | volume = 172 | issue = 7 | pages = 4100–10 | date = April 2004 | pmid = 15034022 | doi = 10.4049/jimmunol.172.7.4100 | doi-access = free }}

Both CD80 and CD86 bind CTLA-4 with higher affinity than CD28. This allows CTLA-4 to outcompete CD28 for CD80/CD86 binding.{{cite journal | vauthors = Walker LS, Sansom DM | title = The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses | journal = Nature Reviews. Immunology | volume = 11 | issue = 12 | pages = 852–63 | date = November 2011 | pmid = 22116087 | doi = 10.1038/nri3108 | s2cid = 9617595 }} 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.{{cite journal | vauthors = Borriello F, Sethna MP, Boyd SD, Schweitzer AN, Tivol EA, Jacoby D, Strom TB, Simpson EM, Freeman GJ, Sharpe AH | title = B7-1 and B7-2 have overlapping, critical roles in immunoglobulin class switching and germinal center formation | journal = Immunity | volume = 6 | issue = 3 | pages = 303–13 | date = March 1997 | pmid = 9075931 | doi = 10.1016/s1074-7613(00)80333-7 | doi-access = free }}

Treg mediation

File:CTLA4 Diagram.png

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,{{cite journal | vauthors = Walker LS, Sansom DM | title = Confusing signals: recent progress in CTLA-4 biology | journal = Trends in Immunology | volume = 36 | issue = 2 | pages = 63–70 | date = February 2015 | pmid = 25582039 | pmc = 4323153 | doi = 10.1016/j.it.2014.12.001 }} 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.{{cite journal | vauthors = Lightman SM, Utley A, Lee KP | title = Survival of Long-Lived Plasma Cells (LLPC): Piecing Together the Puzzle | journal = Frontiers in Immunology | volume = 10 | pages = 965 | date = 2019-05-03 | pmid = 31130955 | pmc = 6510054 | doi = 10.3389/fimmu.2019.00965 | doi-access = free }} 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.{{cite journal | vauthors = Onishi Y, Fehervari Z, Yamaguchi T, Sakaguchi S | title = Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 29 | pages = 10113–8 | date = July 2008 | pmid = 18635688 | pmc = 2481354 | doi = 10.1073/pnas.0711106105 | bibcode = 2008PNAS..10510113O | doi-access = free }}

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".{{cite journal | vauthors = Chen R, Ganesan A, Okoye I, Arutyunova E, Elahi S, Lemieux MJ, Barakat K | title = Targeting B7-1 in immunotherapy | journal = Medicinal Research Reviews | volume = 40 | issue = 2 | pages = 654–682 | date = March 2020 | pmid = 31448437 | doi = 10.1002/med.21632 | s2cid = 201748060 }} 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).{{cite journal | vauthors = Mark DA, Donovan CE, De Sanctis GT, Krinzman SJ, Kobzik L, Linsley PS, Sayegh MH, Lederer J, Perkins DL, Finn PW | title = Both CD80 and CD86 co-stimulatory molecules regulate allergic pulmonary inflammation | journal = International Immunology | volume = 10 | issue = 11 | pages = 1647–55 | date = November 1998 | pmid = 9846693 | doi = 10.1093/intimm/10.11.1647 | doi-access = free }} 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.{{cite journal | vauthors = Parker D | title = CD80/CD86 signaling contributes to the proinflammatory response of Staphylococcus aureus in the airway | journal = Cytokine | volume = 107 | pages = 130–136 | date = July 2018 | pmid = 29402722 | pmc = 5916031 | doi = 10.1016/j.cyto.2018.01.016 }} The costimulatory molecules were also investigated in context of Bronchial Astma,{{cite journal | vauthors = Chen YQ, Shi HZ | title = CD28/CTLA-4--CD80/CD86 and ICOS--B7RP-1 costimulatory pathway in bronchial asthma | journal = Allergy | volume = 61 | issue = 1 | pages = 15–26 | date = January 2006 | pmid = 16364152 | doi = 10.1111/j.1398-9995.2006.01008.x | s2cid = 23564785 }} Treg in cancer,{{cite journal | vauthors = Ohue Y, Nishikawa H | title = Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target? | journal = Cancer Science | volume = 110 | issue = 7 | pages = 2080–2089 | date = July 2019 | pmid = 31102428 | pmc = 6609813 | doi = 10.1111/cas.14069 }} and immunotherapy.{{cite journal | vauthors = Bourque J, Hawiger D | title = Immunomodulatory Bonds of the Partnership between Dendritic Cells and T Cells | journal = Critical Reviews in Immunology | volume = 38 | issue = 5 | pages = 379–401 | date = 2018 | pmid = 30792568 | pmc = 6380512 | doi = 10.1615/CritRevImmunol.2018026790 }}

References

External links

{{UCSC gene info|CD86}}