CD28 (Cluster of Differentiation 28) is aprotein expressed onT cells that provides essentialco-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 variousinterleukins, particularlyIL-6. CD28 serves as a receptor forCD80 (B7.1) andCD86 (B7.2), proteins found onantigen-presenting cells (APCs).
CD28 is the onlyB7 receptor consistently expressed onnaive T cells. In the absence of CD28:B7 interaction, a naive T cell's TCR engagement with anMHC:antigen complex leads toanergy. 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% ofCD8+ T cells and more than 80% ofCD4+ 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 asmemory 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]
CD28 possesses an intracellular domain with several residues that are critical for its effective signaling. The YMNM motif beginning attyrosine 170 in particular is critical for the recruitment ofSH2-domain containing proteins, especiallyPI3K,[9]Grb2[10] andGads. The Y170 residue is important for the induction ofBcl-xL viamTOR and enhancement ofIL-2 transcription viaPKCθ, 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-2mRNA stability but notNF-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 animmune synapse, which results in enhancement of IL-2 mRNA stability. Both are required for full production of IL-2.
CD28 also contains twoproline-rich motifs that are able to bindSH3-containing proteins.Itk andTec 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 andPH 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 kinaseLck which in turn binds to the serine kinasePKC-θ.[11]
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] AsCTLA4, CD28 share highly similarCDR3-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 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 receptorsICOS,CTLA4,PD1, PD1H, andBTLA.[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 asIL-2. CD28 and CTLA4 are very homologous and compete for the same ligand –CD80 andCD86.[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]
The drugTGN1412, which was produced by the German biotech company TeGenero, and unexpectedly causedmultiple organ failure in trials, is asuperagonist of CD28. Unfortunately, it is often ignored that the same receptors also exist on cells other thanlymphocytes. CD28 has also been found to stimulateeosinophil granulocytes where its ligation with anti-CD28 leads to the release ofIL-2,IL4,IL-13 andIFN-γ.[21][22]
It is known that CD28 and CTL4 may be critical regulators ofautoimmune 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´ antibodyFR104,[26] or an octapeptide AB103, which prevents CD28 homodimerization.[27]
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^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.PMID7737275.S2CID23540587.
^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.PMID11861596.
^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.PMID7882171.
Bour-Jordan H, Blueston JA (January 2002). "CD28 function: a balance of costimulatory and regulatory signals".Journal of Clinical Immunology.22 (1):1–7.doi:10.1023/A:1014256417651.PMID11958588.S2CID38060684.
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