CD28 explained

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.[1] [2] [3] [4] 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.[5]

As a homodimer of two chains with Ig domains, CD28 binds B7 molecules on APCs and can promote T cells proliferation and differentiation, stimulate production of growth factor, and induces the expression of anti-apoptotic proteins.[6] According to several studies, after birth, all human cells express CD28. However, in adults, 20-30% of CD8+ T cells lose CD28 expression, whereas in the elderly (+80 years) up to 50-60% of CD8+ cells lose the ability to express CD28.[7] But these statements only suggest that loss of CD28 expression marks functional differentiation to cytotoxic memory cells within clonal expansions.[8]

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 emphasized by the fact that antagonists of co-stimulatory molecules disrupt the immune responses both in vitro and in vivo.[9] But as mentioned earlier, during the course of activation e.g. TMs lose this molecule and assume a CD28-independent existence.[10]

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,[11] Grb2[12] 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.[13]

Structure

The first structure of CD28 was obtained in 2005 by the T-cell biology group at the University of Oxford.[14]

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.[15] As CTLA4, CD28 share highly similar CDR3-analogous loops.[16] 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.[14]

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.[17] 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.[18] CTLA4 binds CD80 and CD86 always stronger than CD28, which allows CTLA4 to compete with CD28 for ligand and suppress effector T cells responses.[19] 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.[20] [21] 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.[22]

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.[23] [24]

It is known that CD28 and CTL4 may be critical regulators of autoimmune diseases in mouse model.[25] [26] 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,[27] a monoclonal anti-CD28 Fab´ antibody FR104,[28] or an octapeptide AB103, which prevents CD28 homodimerization.[29]

Interactions

CD28 has been shown to interact with:

See also

Further reading

External links

Notes and References

  1. 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. 10.4049/jimmunol.169.5.2292. 12193694. 22737782. 0022-1767. free.
  2. 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. 10.1084/jem.20110040. 21690252. 3135367. 1540-9538.
  3. 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. 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. 10.1002/1521-4141(200105)31:5<1536::aid-immu1536>3.0.co;2-8. 11465111. 22349635 . 0014-2980.
  4. 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. 10.1111/j.1365-2222.2004.02036.x. 15347370. 21120027. 0954-7894.
  5. 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. 10.1016/j.cellimm.2011.06.018. 21745657. 0008-8749.
  6. Esensten. Jonathan H.. Helou. Ynes A.. Chopra. Gaurav. Weiss. Arthur. Bluestone. Jeffrey A.. May 2016. CD28 Costimulation: From Mechanism to Therapy. Immunity. en. 44. 5. 973–988. 10.1016/j.immuni.2016.04.020. 27192564. 4932896.
  7. 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. 10.1046/j.1365-2567.1996.d01-689.x. 8881749 . 1456634 . 0019-2805.
  8. 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. en. 94. 3. 160–172. 10.1006/clim.1999.4832. 10692235.
  9. Book: Chapel, Helen. Základy klinické imunologie : 6. vydání. 2018. Mansel Haeney, Siraj A. Misbah, Neil Snowden, Vojtěch Thon. 978-80-7553-396-8. Praha. 1031053171.
  10. 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. en. 14. 11. 2460–2466. 10.1111/ajt.12937. 4886707. 25323029.
  11. Prasad KV, Cai YC, Raab M, Duckworth B, Cantley L, Shoelson SE, Rudd CE . 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 . March 1994 . 8146197 . 43465 . 10.1073/pnas.91.7.2834 . 1994PNAS...91.2834P . free .
  12. Schneider H, Cai YC, Prasad KV, Shoelson SE, Rudd CE . T cell antigen CD28 binds to the GRB-2/SOS complex, regulators of p21ras . European Journal of Immunology . 25 . 4 . 1044–50 . April 1995 . 7737275 . 10.1002/eji.1830250428 . 23540587 .
  13. Kong KF, Yokosuka T, Canonigo-Balancio AJ, Isakov N, Saito T, Altman A . 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 . October 2011 . 21964608 . 3197934 . 10.1038/ni.2120 .
  14. Evans EJ, Esnouf RM, Manso-Sancho R, Gilbert RJ, James JR, Yu C, Fennelly JA, Vowles C, Hanke T, Walse B, Hünig T, Sørensen P, Stuart DI, Davis SJ . 6 . Crystal structure of a soluble CD28-Fab complex . Nature Immunology . 6 . 3 . 271–9 . March 2005 . 15696168 . 10.1038/ni1170 . 23630078 .
  15. Carreno BM, Collins M . 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 . April 2002 . 11861596 . 10.1146/annurev.immunol.20.091101.091806 .
  16. Zhang X, Schwartz JC, Almo SC, Nathenson SG . 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 . March 2003 . 12606712 . 10.1073/pnas.252771499 . 151384 . 2003PNAS..100.2586Z . free .
  17. Chen L, Flies DB . Molecular mechanisms of T cell co-stimulation and co-inhibition . Nature Reviews. Immunology . 13 . 4 . 227–42 . April 2013 . 23470321 . 10.1038/nri3405 . 3786574 .
  18. Linsley PS, Clark EA, Ledbetter JA . 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 . July 1990 . 2164219 . 10.1073/pnas.87.13.5031 . 54255 . 1990PNAS...87.5031L . free .
  19. Engelhardt JJ, Sullivan TJ, Allison JP . CTLA-4 overexpression inhibits T cell responses through a CD28-B7-dependent mechanism . Journal of Immunology . 177 . 2 . 1052–61 . July 2006 . 16818761 . 10.4049/jimmunol.177.2.1052 . 7990944 . free .
  20. Krummel MF, Allison JP . CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation . The Journal of Experimental Medicine . 182 . 2 . 459–65 . August 1995 . 7543139 . 10.1084/jem.182.2.459 . 2192127 .
  21. Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, Thompson CB, Bluestone JA . 6 . CTLA-4 can function as a negative regulator of T cell activation . Immunity . 1 . 5 . 405–13 . August 1994 . 7882171 . 10.1016/1074-7613(94)90071-x .
  22. Linterman MA, Rigby RJ, Wong R, Silva D, Withers D, Anderson G, Verma NK, Brink R, Hutloff A, Goodnow CC, Vinuesa CG . 6 . Roquin differentiates the specialized functions of duplicated T cell costimulatory receptor genes CD28 and ICOS . Immunity . 30 . 2 . 228–41 . February 2009 . 19217324 . 10.1016/j.immuni.2008.12.015 . free .
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  24. Woerly G, Lacy P, Younes AB, Roger N, Loiseau S, Moqbel R, Capron M . Human eosinophils express and release IL-13 following CD28-dependent activation . Journal of Leukocyte Biology . 72 . 4 . 769–79 . October 2002 . 12377947 . 10.1189/jlb.72.4.769 . 10820672 . free .
  25. Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, Bluestone JA . B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes . Immunity . 12 . 4 . 431–40 . April 2000 . 10795741 . 10.1016/s1074-7613(00)80195-8 . free .
  26. 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. 10.1016/1074-7613(95)90125-6. 7584144 . 46680106 . 1074-7613. free.
  27. Pastor F, Soldevilla MM, Villanueva H, Kolonias D, Inoges S, de Cerio AL, Kandzia R, Klimyuk V, Gleba Y, Gilboa E, Bendandi M . 6 . CD28 aptamers as powerful immune response modulators . Molecular Therapy: Nucleic Acids . 2 . e98 . June 2013 . 6 . 23756353 . 10.1038/mtna.2013.26 . 3696906 .
  28. Poirier N, Mary C, Dilek N, Hervouet J, Minault D, Blancho G, Vanhove B . Preclinical efficacy and immunological safety of FR104, an antagonist anti-CD28 monovalent Fab' antibody . American Journal of Transplantation . 12 . 10 . 2630–40 . October 2012 . 22759318 . 10.1111/j.1600-6143.2012.04164.x . 715661 . free .
  29. Mirzoeva S, Paunesku T, Wanzer MB, Shirvan A, Kaempfer R, Woloschak GE, Small W . 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 . 2014-07-23 . 25054224 . 10.1371/journal.pone.0101161 . 4108308 . 2014PLoSO...9j1161M . free .
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