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CD28

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CD28
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCD28, Tp44, CD28 molecule
External IDsOMIM: 186760; MGI: 88327; HomoloGene: 4473; GeneCards: CD28; OMA:CD28 - orthologs
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 a protein expressed on T cells that provides essential co-stimulatory signals required for T cell activation and survival. When T cells are stimulated through CD28 in conjunction with the T-cell receptor (TCR), it enhances the production of various interleukins, particularly IL-6. CD28 serves as a receptor for CD80 (B7.1) and CD86 (B7.2), proteins found on antigen-presenting cells (APCs).

CD28 is the only B7 receptor consistently expressed on naive T cells. In the absence of CD28:B7 interaction, a naive T cell's TCR engagement with an MHC:antigen complex leads to anergy. CD28 is also expressed on bone marrow stromal cells, plasma cells, neutrophils, and eosinophils, although its function in these cells is not fully understood.[5]

Typically, CD28 is expressed on about 50% of CD8+ T cells and more than 80% of CD4+ T cells in humans. However, some T cells lose CD28 expression during activation, particularly antigen-experienced T cells, which can be re-activated independently of CD28. These CD28− T cells are often antigen-specific, terminally differentiated, and categorized as memory T cells (TMs). The proportion of CD28− T cells increases with age.[6]

As a homodimer with Ig domains, CD28 binds B7 molecules on APCs, promoting T cell proliferation, differentiation, growth factor production, and the expression of anti-apoptotic proteins.[7] While CD28 is crucial for T cell activation, particularly in initial immune responses, some antigen-experienced T cells can function without it, marking their differentiation into cytotoxic memory cells.[8]

Signaling

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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,[9] Grb2[10] 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.[11]

Structure

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The structure of the human 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.[12] As CTLA4, CD28 share highly similar CDR3-analogous loops.[13] 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

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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.[15] 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.[16] CTLA4 binds CD80 and CD86 always stronger than CD28, which allows CTLA4 to compete with CD28 for ligand and suppress effector T cells responses.[17] 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.[18][19] 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.[20]

As a drug target

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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.[21][22]

It is known that CD28 and CTL4 may be critical regulators of autoimmune diseases in mouse model.[23][24] 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,[25] a monoclonal anti-CD28 Fab´ antibody FR104,[26] or an octapeptide AB103, which prevents CD28 homodimerization.[27]

Interactions

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CD28 has been shown to interact with:

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000178562 – Ensembl, May 2017
  2. ^ a b c 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 K, Stephan RP, Apilado RG, Lill-Elghanian DA, Lee KP, Saha B, et al. (September 2002). "Expression of CD28 by bone marrow stromal cells and its involvement in B lymphopoiesis". Journal of Immunology. 169 (5): 2292–2302. doi:10.4049/jimmunol.169.5.2292. PMID 12193694. S2CID 22737782.
  6. ^ Diaz D, Chara L, Chevarria J, Ubeda M, Muñoz L, Barcenilla H, et al. (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. PMID 21745657.
  7. ^ Esensten JH, Helou YA, Chopra G, Weiss A, Bluestone JA (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.
  8. ^ Mou D, Espinosa J, Lo DJ, Kirk AD (November 2014). "CD28 negative T cells: is their loss our gain?". American Journal of Transplantation. 14 (11): 2460–2466. doi:10.1111/ajt.12937. PMC 4886707. PMID 25323029.
  9. ^ Prasad KV, Cai YC, Raab M, Duckworth B, Cantley L, Shoelson SE, et al. (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): 2834–2838. Bibcode:1994PNAS...91.2834P. doi:10.1073/pnas.91.7.2834. PMC 43465. PMID 8146197.
  10. ^ 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): 1044–1050. doi:10.1002/eji.1830250428. PMID 7737275. S2CID 23540587.
  11. ^ 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): 1105–1112. doi:10.1038/ni.2120. PMC 3197934. PMID 21964608.
  12. ^ 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.
  13. ^ 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): 2586–2591. Bibcode:2003PNAS..100.2586Z. doi:10.1073/pnas.252771499. PMC 151384. PMID 12606712.
  14. ^ 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.
  15. ^ Chen L, Flies DB (April 2013). "Molecular mechanisms of T cell co-stimulation and co-inhibition". Nature Reviews. Immunology. 13 (4): 227–242. doi:10.1038/nri3405. PMC 3786574. PMID 23470321.
  16. ^ 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): 5031–5035. Bibcode:1990PNAS...87.5031L. doi:10.1073/pnas.87.13.5031. PMC 54255. PMID 2164219.
  17. ^ 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): 1052–1061. doi:10.4049/jimmunol.177.2.1052. PMID 16818761. S2CID 7990944.
  18. ^ 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): 459–465. doi:10.1084/jem.182.2.459. PMC 2192127. PMID 7543139.
  19. ^ 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): 405–413. doi:10.1016/1074-7613(94)90071-x. PMID 7882171.
  20. ^ 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): 228–241. doi:10.1016/j.immuni.2008.12.015. PMID 19217324.
  21. ^ 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): 487–495. doi:10.1084/jem.190.4.487. PMC 2195599. PMID 10449520.
  22. ^ Woerly G, Lacy P, Younes AB, Roger N, Loiseau S, Moqbel R, et al. (October 2002). "Human eosinophils express and release IL-13 following CD28-dependent activation". Journal of Leukocyte Biology. 72 (4): 769–779. doi:10.1189/jlb.72.4.769. PMID 12377947. S2CID 10820672.
  23. ^ Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, et al. (April 2000). "B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes". Immunity. 12 (4): 431–440. doi:10.1016/s1074-7613(00)80195-8. PMID 10795741.
  24. ^ 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. PMID 7584144. S2CID 46680106.
  25. ^ 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.
  26. ^ Poirier N, Mary C, Dilek N, Hervouet J, Minault D, Blancho G, et al. (October 2012). "Preclinical efficacy and immunological safety of FR104, an antagonist anti-CD28 monovalent Fab' antibody". American Journal of Transplantation. 12 (10): 2630–2640. doi:10.1111/j.1600-6143.2012.04164.x. PMID 22759318. S2CID 715661.
  27. ^ Mirzoeva S, Paunesku T, Wanzer MB, Shirvan A, Kaempfer R, Woloschak GE, et al. (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.
  28. ^ 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): 5805–5814. doi:10.4049/jimmunol.164.11.5805. PMID 10820259. S2CID 25739159.
  29. ^ 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): 21194–21202. doi:10.1074/jbc.273.33.21194. PMID 9694876. S2CID 39280280.
  30. ^ 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): 1591–1598. doi:10.1074/jbc.271.3.1591. PMID 8576157. S2CID 37740924.
  31. ^ 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): 9403–9409. doi:10.1074/jbc.271.16.9403. PMID 8621607. S2CID 12566111.

Further reading

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