CD28
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCD28, Tp44, CD28 molecule
External IDsOMIM: 186760 MGI: 88327 HomoloGene: 4473 GeneCards: CD28
Orthologs
SpeciesHumanMouse
Entrez

940

12487

Ensembl

ENSG00000178562

ENSMUSG00000026012

UniProt

P10747

P31041

RefSeq (mRNA)

NM_001243077
NM_001243078
NM_006139

NM_007642

RefSeq (protein)

NP_001230006
NP_001230007
NP_006130

NP_031668

Location (UCSC)Chr 2: 203.71 – 203.74 MbChr 1: 60.76 – 60.81 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

CD28 (Cluster of Differentiation 28) is one of the proteins expressed on T cells that provide co-stimulatory signals required for T cell activation and survival. T cell stimulation through CD28 in addition to the T-cell receptor (TCR) can provide a potent signal for the production of various interleukins (IL-6 in particular).

CD28 is the receptor for CD80 (B7.1) and CD86 (B7.2) proteins. When activated by Toll-like receptor ligands, the CD80 expression is upregulated in antigen-presenting cells (APCs). The CD86 expression on antigen-presenting cells is constitutive (expression is independent of environmental factors).

CD28 is the only B7 receptor constitutively expressed on naive T cells. Association of the TCR of a naive T cell with MHC:antigen complex without CD28:B7 interaction results in a T cell that is anergic.

Furthermore, CD28 was also identified on bone marrow stromal cells, plasma cells, neutrophils and eosinophils, but the functional importance of CD28 on these cells is not completely understood.[5][6][7][8] It is generally reported, that CD28 is expressed on 50% of CD8+ T cells and more than 80% CD4+ T cells in human, but during the course of activation some T cells lose this molecule. Some antigen-experienced T cells lose CD28 and subsequently can be re-activated without CD28 engagement. These CD28− T cells have generally been characterized as antigen specific and terminally differentiated, and are often described as being memory T cells (TMs). In addition, the level of positive CD28 decreases with age.[9]

As a homodimer of two chains with Ig domains binds B7 molecules on APCs and it can promotes T cells proliferation and differentiation, stimulates production of growth factors and induces the expression of anti-apoptotic proteins.[10] According to several studies, after birth, all human cells express CD28. But in adult, 20-30% of CD8+ T cells lose the ability of CD28 expression, whereas in the elderly (+80 years) up to 50-60% of CD8+ cells lose the ability of CD28 expression.[11] But these statements only suggest that loss of CD28 expression marks functional differentiation to cytotoxic memory cells within clonal expansions.[12]

In general, CD28 is a primary costimulatory molecule for T cell activation. But effective co-stimulation is essential only for some T cell activation. In this case, in the absence of co-stimulatory signals, the interaction of dendritic and T cells leads to T cell anergy. The importance of the costimulatory pathway is underlined by the fact that antagonists of co-stimulatory molecules disrupt the immune responses both in vitro and in vivo.[13] But as mentioned earlier, during the course of activation e.g. TMs lose this molecule and assume a CD28-independent existence.[14]

Signaling

CD28 possesses an intracellular domain with several residues that are critical for its effective signaling. The YMNM motif beginning at tyrosine 170 in particular is critical for the recruitment of SH2-domain containing proteins, especially PI3K,[15] Grb2[16] and Gads. The Y170 residue is important for the induction of Bcl-xL via mTOR and enhancement of IL-2 transcription via PKCθ, but has no effect on proliferation and results a slight reduction in IL-2 production. The N172 residue (as part of the YMNM) is important for the binding of Grb2 and Gads and seems to be able to induce IL-2 mRNA stability but not NF-κB translocation. The induction of NF-κB seems to be much more dependent on the binding of Gads to both the YMNM and the two proline-rich motifs within the molecule. However, mutation of the final amino acid of the motif, M173, which is unable to bind PI3K but is able to bind Grb2 and Gads, gives little NF-κB or IL-2, suggesting that those Grb2 and Gads are unable to compensate for the loss of PI3K. IL-2 transcription appears to have two stages; a Y170-dependent, PI3K-dependent initial phase which allows transcription and a PI3K-independent second phase which is dependent on formation of an immune synapse, which results in enhancement of IL-2 mRNA stability. Both are required for full production of IL-2.

CD28 also contains two proline-rich motifs that are able to bind SH3-containing proteins. Itk and Tec are able to bind to the N-terminal of these two motifs which immediately succeeds the Y170 YMNM; Lck binds the C-terminal. Both Itk and Lck are able to phosphorylate the tyrosine residues which then allow binding of SH2 containing proteins to CD28. Binding of Tec to CD28 enhances IL-2 production, dependent on binding of its SH3 and PH domains to CD28 and PIP3 respectively. The C-terminal proline-rich motif in CD28 is important for bringing Lck and lipid rafts into the immune synapse via filamin-A. Mutation of the two prolines within the C-terminal motif results in reduced proliferation and IL-2 production but normal induction of Bcl-xL. Phosphorylation of a tyrosine within the PYAP motif (Y191 in the mature human CD28) forms a high affinity-binding site for the SH2 domain of the src kinase Lck which in turn binds to the serine kinase PKC-θ.[17]

Structure

The first structure of CD28 was obtained in 2005 by the T-cell biology group at the University of Oxford.[18]

The structure of the CD28 protein contains 220 amino acids, encoded by a gene consisting of four exons. It is a glycosylated, disulfide-linked homodimer of 44 kDa expressed on the cell surface. The structure contains paired domains of the V-set immunoglobulin superfamilies (IgSF). These domains are linked to individual transmembrane domains and cytoplasmic domains that contain critical signaling motifs.[19] As CTLA4, CD28 share highly similar CDR3-analogous loops.[20] In the CD28-CD80 complex, the two CD80 molecules converge such that their membrane proximal domains collide sterically, despite the availability of both ligand binding sites for CD28.[18]

CD28 family members

CD28 belongs into group members of a subfamily of costimulatory molecules that are characterized by an extracellular variable immunoglobulin-like domain. Members of this subfamily also include homologous receptors ICOS, CTLA4, PD1, PD1H, and BTLA.[21] Nevertheless, only CD28 is expressed constitutively on mouse T cells, whereas ICOS and CTLA4 are induce by T cells receptor stimulation and in response to cytokines such as IL-2. CD28 and CTLA4 are very homologous and compete for the same ligand – CD80 and CD86.[22] CTLA4 binds CD80 and CD86 always stronger than CD28, which allows CTLA4 to compete with CD28 for ligand and suppress effector T cells responses.[23] But it was shown that CD28 and CTLA4 have opposite effect on the T cells stimulation. CD28 acts as a activator and CTLA4 acts as inhibitor.[24][25] ICOS and CD28 are also closely related genes, but they cannot substitute from one another in function. The opposing roles of CD28 and ICOS compared to CTLA4 cause that these receptors act as a rheostat for the immune response through competitive pro- and anti-inflammatory effects.[26]

As a drug target

The drug TGN1412, which was produced by the German biotech company TeGenero, and unexpectedly caused multiple organ failure in trials, is a superagonist of CD28. Unfortunately, it is often ignored that the same receptors also exist on cells other than lymphocytes. CD28 has also been found to stimulate eosinophil granulocytes where its ligation with anti-CD28 leads to the release of IL-2, IL4, IL-13 and IFN-γ.[27][28]

It is known that CD28 and CTL4 may be critical regulators autoimmune diseases in mouse model.[29][30] But there is less data from patients on the role of CD28 in human diseases.

Other potential drugs in pre-clinical development are agonist CD28 aptamers with immunostimulatory properties in a mouse tumor model,[31] a monoclonal anti-CD28 Fab´ antibody FR104,[32] or an octapeptide AB103, which prevents CD28 homodimerization.[33]

Interactions

CD28 has been shown to interact with:

See also

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000178562 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000026012 - 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. ↑ Gray Parkin, Kirstin; Stephan, Robert P.; Apilado, Ron-Gran; Lill-Elghanian, Deborah A.; Lee, Kelvin P.; Saha, Bhaskar; Witte, Pamela L. (2002-09-01). "Expression of CD28 by Bone Marrow Stromal Cells and Its Involvement in B Lymphopoiesis". The Journal of Immunology. 169 (5): 2292–2302. doi:10.4049/jimmunol.169.5.2292. ISSN 0022-1767. PMID 12193694. S2CID 22737782.
  6. ↑ Rozanski, Cheryl H.; Arens, Ramon; Carlson, Louise M.; Nair, Jayakumar; Boise, Lawrence H.; Chanan-Khan, Asher A.; Schoenberger, Stephen P.; Lee, Kelvin P. (2011-06-20). "Sustained antibody responses depend on CD28 function in bone marrow–resident plasma cells". Journal of Experimental Medicine. 208 (7): 1435–1446. doi:10.1084/jem.20110040. ISSN 1540-9538. PMC 3135367. PMID 21690252.
  7. ↑ Venuprasad, K.; Parab, Pradeep; Prasad, D. V. R.; Sharma, Satyan; Banerjee, Pinaki P.; Deshpande, Manisha; Mitra, Dipendra K.; Pal, Subrata; Bhadra, Ranjan; Mitra, Debashis; Saha, Bhaskar (May 2001). <1536::aid-immu1536>3.0.co;2-8 "Immunobiology of CD28 expression on human neutrophils. I. CD28 regulates neutrophil migration by modulating CXCR-1 expression". European Journal of Immunology. 31 (5): 1536–1543. doi:10.1002/1521-4141(200105)31:5<1536::aid-immu1536>3.0.co;2-8. ISSN 0014-2980. PMID 11465111. S2CID 22349635.
  8. ↑ Woerly, G.; Decot, V.; Loiseau, S.; Loyens, M.; Chihara, J.; Ono, N.; Capron, M. (September 2004). "CD28 and secretory immunoglobulin A-dependent activation of eosinophils: inhibition of mediator release by the anti-allergic drug, suplatast tosilate". Clinical & Experimental Allergy. 34 (9): 1379–1387. doi:10.1111/j.1365-2222.2004.02036.x. ISSN 0954-7894. PMID 15347370. S2CID 21120027.
  9. ↑ Diaz, David; Chara, Luis; Chevarria, Julio; Ubeda, Maria; Muñoz, Leticia; Barcenilla, Hugo; Sánchez, Miguel Angel; Moreno, Zaida; Monserrat, Jorge; Albillos, Agustin; Prieto, Alfredo (2011). "Loss of surface antigens is a conserved feature of apoptotic lymphocytes from several mammalian species". Cellular Immunology. 271 (1): 163–172. doi:10.1016/j.cellimm.2011.06.018. ISSN 0008-8749. PMID 21745657.
  10. ↑ Esensten, Jonathan H.; Helou, Ynes A.; Chopra, Gaurav; Weiss, Arthur; Bluestone, Jeffrey A. (May 2016). "CD28 Costimulation: From Mechanism to Therapy". Immunity. 44 (5): 973–988. doi:10.1016/j.immuni.2016.04.020. PMC 4932896. PMID 27192564.
  11. ↑ FAGNONI, F. F.; VESCOVINI, R.; MAZZOLA, M.; BOLOGNA, G.; NIGRO, E.; LAVAGETTO, G.; FRANCESCHI, C.; PASSERI, M.; SANSONI, P. (August 1996). "Expansion of cytotoxic CD8 + CD28 − T cells in healthy ageing people, including centenarians". Immunology. 88 (4): 501–507. doi:10.1046/j.1365-2567.1996.d01-689.x. ISSN 0019-2805. PMC 1456634. PMID 8881749.
  12. ↑ Chamberlain, Winston D.; Falta, Michael T.; Kotzin, Brian L. (March 2000). "Functional Subsets within Clonally Expanded CD8+ Memory T Cells in Elderly Humans". Clinical Immunology. 94 (3): 160–172. doi:10.1006/clim.1999.4832. PMID 10692235.
  13. ↑ Chapel, Helen (2018). Základy klinické imunologie : 6. vydání. Mansel Haeney, Siraj A. Misbah, Neil Snowden, Vojtěch Thon. Praha. ISBN 978-80-7553-396-8. OCLC 1031053171.{{cite book}}: CS1 maint: location missing publisher (link)
  14. ↑ Mou, D.; Espinosa, J.; Lo, D. J.; Kirk, A. D. (November 2014). "CD28 Negative T Cells: Is Their Loss Our Gain?: CD28 Negative T Cells". American Journal of Transplantation. 14 (11): 2460–2466. doi:10.1111/ajt.12937. PMC 4886707. PMID 25323029.
  15. ↑ Prasad KV, Cai YC, Raab M, Duckworth B, Cantley L, Shoelson SE, Rudd CE (March 1994). "T-cell antigen CD28 interacts with the lipid kinase phosphatidylinositol 3-kinase by a cytoplasmic Tyr(P)-Met-Xaa-Met motif". Proceedings of the National Academy of Sciences of the United States of America. 91 (7): 2834–8. Bibcode:1994PNAS...91.2834P. doi:10.1073/pnas.91.7.2834. PMC 43465. PMID 8146197.
  16. ↑ Schneider H, Cai YC, Prasad KV, Shoelson SE, Rudd CE (April 1995). "T cell antigen CD28 binds to the GRB-2/SOS complex, regulators of p21ras". European Journal of Immunology. 25 (4): 1044–50. doi:10.1002/eji.1830250428. PMID 7737275. S2CID 23540587.
  17. ↑ Kong KF, Yokosuka T, Canonigo-Balancio AJ, Isakov N, Saito T, Altman A (October 2011). "A motif in the V3 domain of the kinase PKC-θ determines its localization in the immunological synapse and functions in T cells via association with CD28". Nature Immunology. 12 (11): 1105–12. doi:10.1038/ni.2120. PMC 3197934. PMID 21964608.
  18. 1 2 Evans EJ, Esnouf RM, Manso-Sancho R, Gilbert RJ, James JR, Yu C, et al. (March 2005). "Crystal structure of a soluble CD28-Fab complex". Nature Immunology. 6 (3): 271–9. doi:10.1038/ni1170. PMID 15696168. S2CID 23630078.
  19. ↑ Carreno BM, Collins M (April 2002). "The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses". Annual Review of Immunology. 20 (1): 29–53. doi:10.1146/annurev.immunol.20.091101.091806. PMID 11861596.
  20. ↑ Zhang X, Schwartz JC, Almo SC, Nathenson SG (March 2003). "Crystal structure of the receptor-binding domain of human B7-2: insights into organization and signaling". Proceedings of the National Academy of Sciences of the United States of America. 100 (5): 2586–91. Bibcode:2003PNAS..100.2586Z. doi:10.1073/pnas.252771499. PMC 151384. PMID 12606712.
  21. ↑ 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.
  22. ↑ Linsley PS, Clark EA, Ledbetter JA (July 1990). "T-cell antigen CD28 mediates adhesion with B cells by interacting with activation antigen B7/BB-1". Proceedings of the National Academy of Sciences of the United States of America. 87 (13): 5031–5. Bibcode:1990PNAS...87.5031L. doi:10.1073/pnas.87.13.5031. PMC 54255. PMID 2164219.
  23. ↑ Engelhardt JJ, Sullivan TJ, Allison JP (July 2006). "CTLA-4 overexpression inhibits T cell responses through a CD28-B7-dependent mechanism". Journal of Immunology. 177 (2): 1052–61. doi:10.4049/jimmunol.177.2.1052. PMID 16818761. S2CID 7990944.
  24. ↑ Krummel MF, Allison JP (August 1995). "CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation". The Journal of Experimental Medicine. 182 (2): 459–65. doi:10.1084/jem.182.2.459. PMC 2192127. PMID 7543139.
  25. ↑ Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, et al. (August 1994). "CTLA-4 can function as a negative regulator of T cell activation". Immunity. 1 (5): 405–13. doi:10.1016/1074-7613(94)90071-x. PMID 7882171.
  26. ↑ Linterman MA, Rigby RJ, Wong R, Silva D, Withers D, Anderson G, et al. (February 2009). "Roquin differentiates the specialized functions of duplicated T cell costimulatory receptor genes CD28 and ICOS". Immunity. 30 (2): 228–41. doi:10.1016/j.immuni.2008.12.015. PMID 19217324.
  27. ↑ Woerly G, Roger N, Loiseau S, Dombrowicz D, Capron A, Capron M (August 1999). "Expression of CD28 and CD86 by human eosinophils and role in the secretion of type 1 cytokines (interleukin 2 and interferon gamma): inhibition by immunoglobulin a complexes". The Journal of Experimental Medicine. 190 (4): 487–95. doi:10.1084/jem.190.4.487. PMC 2195599. PMID 10449520.
  28. ↑ Woerly G, Lacy P, Younes AB, Roger N, Loiseau S, Moqbel R, Capron M (October 2002). "Human eosinophils express and release IL-13 following CD28-dependent activation". Journal of Leukocyte Biology. 72 (4): 769–79. doi:10.1189/jlb.72.4.769. PMID 12377947. S2CID 10820672.
  29. ↑ Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, Bluestone JA (April 2000). "B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes". Immunity. 12 (4): 431–40. doi:10.1016/s1074-7613(00)80195-8. PMID 10795741.
  30. ↑ Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH (November 1995). "Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4". Immunity. 3 (5): 541–547. doi:10.1016/1074-7613(95)90125-6. ISSN 1074-7613. PMID 7584144. S2CID 46680106.
  31. ↑ Pastor F, Soldevilla MM, Villanueva H, Kolonias D, Inoges S, de Cerio AL, et al. (June 2013). "CD28 aptamers as powerful immune response modulators". Molecular Therapy: Nucleic Acids. 2 (6): e98. doi:10.1038/mtna.2013.26. PMC 3696906. PMID 23756353.
  32. ↑ Poirier N, Mary C, Dilek N, Hervouet J, Minault D, Blancho G, Vanhove B (October 2012). "Preclinical efficacy and immunological safety of FR104, an antagonist anti-CD28 monovalent Fab' antibody". American Journal of Transplantation. 12 (10): 2630–40. doi:10.1111/j.1600-6143.2012.04164.x. PMID 22759318. S2CID 715661.
  33. ↑ Mirzoeva S, Paunesku T, Wanzer MB, Shirvan A, Kaempfer R, Woloschak GE, Small W (2014-07-23). "Single administration of p2TA (AB103), a CD28 antagonist peptide, prevents inflammatory and thrombotic reactions and protects against gastrointestinal injury in total-body irradiated mice". PLOS ONE. 9 (7): e101161. Bibcode:2014PLoSO...9j1161M. doi:10.1371/journal.pone.0101161. PMC 4108308. PMID 25054224.
  34. ↑ Ellis JH, Ashman C, Burden MN, Kilpatrick KE, Morse MA, Hamblin PA (June 2000). "GRID: a novel Grb-2-related adapter protein that interacts with the activated T cell costimulatory receptor CD28". Journal of Immunology. 164 (11): 5805–14. doi:10.4049/jimmunol.164.11.5805. PMID 10820259. S2CID 25739159.
  35. ↑ Okkenhaug K, Rottapel R (August 1998). "Grb2 forms an inducible protein complex with CD28 through a Src homology 3 domain-proline interaction". The Journal of Biological Chemistry. 273 (33): 21194–202. doi:10.1074/jbc.273.33.21194. PMID 9694876. S2CID 39280280.
  36. ↑ Nunès JA, Truneh A, Olive D, Cantrell DA (January 1996). "Signal transduction by CD28 costimulatory receptor on T cells. B7-1 and B7-2 regulation of tyrosine kinase adaptor molecules". The Journal of Biological Chemistry. 271 (3): 1591–8. doi:10.1074/jbc.271.3.1591. PMID 8576157. S2CID 37740924.
  37. ↑ Pagès F, Ragueneau M, Klasen S, Battifora M, Couez D, Sweet R, et al. (April 1996). "Two distinct intracytoplasmic regions of the T-cell adhesion molecule CD28 participate in phosphatidylinositol 3-kinase association". The Journal of Biological Chemistry. 271 (16): 9403–9. doi:10.1074/jbc.271.16.9403. PMID 8621607. S2CID 12566111.

Further reading

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