CD28

CD28
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1YJD, 3WA4, 5AUL
Identifiers
Aliases	CD28, Tp44, CD28 molecule
External IDs	OMIM: 186760; MGI: 88327; HomoloGene: 4473; GeneCards: CD28; OMA:CD28 - orthologs
Gene location (Human) Chr. Chromosome 2 (human) Band 2q33.2 Start 203,706,475 bp End 203,738,912 bp
Gene location (Mouse) Chr. Chromosome 1 (mouse) Band 1 C2|1 30.52 cM Start 60,755,959 bp End 60,812,518 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in lymph node appendix blood granulocyte epithelium of colon gallbladder amniotic fluid thymus tonsil spleen Top expressed in thymus blood spleen vastus lateralis muscle mesenteric lymph nodes triceps brachii muscle temporal muscle subcutaneous adipose tissue sternocleidomastoid muscle morula More reference expression data BioGPS More reference expression data
Gene ontology Molecular function coreceptor activity protease binding protein binding identical protein binding protein kinase binding phosphatidylinositol-4,5-bisphosphate 3-kinase activity Cellular component integral component of membrane cytosol membrane plasma membrane integral component of plasma membrane immunological synapse external side of plasma membrane cell surface protein complex involved in cell adhesion Biological process regulatory T cell differentiation regulation of regulatory T cell differentiation T cell costimulation mitigation of host defenses by virus positive regulation of translation negative regulation of gene expression negative thymic T cell selection cell surface receptor signaling pathway positive regulation of gene expression humoral immune response positive regulation of T cell proliferation positive regulation of alpha-beta T cell proliferation immune response apoptotic signaling pathway positive regulation of phosphatidylinositol 3-kinase signaling positive regulation of isotype switching to IgG isotypes positive regulation of viral genome replication T cell receptor signaling pathway positive regulation of mitotic nuclear division positive regulation of inflammatory response to antigenic stimulus positive regulation of transcription by RNA polymerase II positive regulation of interleukin-10 production phosphatidylinositol phosphate biosynthetic process positive regulation of interleukin-4 production positive regulation of protein kinase B signaling T cell activation negative regulation of apoptotic process regulation of T cell proliferation immune system process Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr 1: 60.76 – 60.81 Mb PubMed search
Wikidata
View/Edit Human View/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.

CD28 is also expressed on 50 % of CD8+ T cells and more than 90 % CD4+ T cells in human. 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. Expression of CD28 was identified on bone marrow stromal cells, plasma cells, neutrophils and eosinophils, but the level of positive CD28 decreases with age. For example after birth, all human cells express CD28 cells. 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.

Effective co-stimulation is essential for T cell activation. 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.

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, Grb2 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.

Structure

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

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. As CTLA4, CD28 share highly similar CDR3-analogous loops. 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.

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. 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. CTLA4 binds CD80 and CD86 always stronger than CD28, which allows CTLA4 to compete with CD28 for ligand and suppress effector T cells responses. But it was showed that CD28 and CTL4 have opposite effect on the T cells stimulation. CD28 acts as a activator and CTL4 acts as inhibitor. 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.

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.

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

Interactions

CD28 has been shown to interact with:

• GRAP2,
• Grb2, and
• PIK3R1.

See also

• List of human clusters of differentiation

Further reading

• Esensten, J. H., Helou, Y. A., Chopra, G., Weiss, A., & Bluestone, J. A. (2016). "CD28 costimulation: from mechanism to therapy". Immunity. 44: 973–988.{{cite journal}}: CS1 maint: multiple names: authors list (link)
• Lenschow DJ, Walunas TL, Bluestone JA (1996). "CD28/B7 system of T cell costimulation". Annu. Rev. Immunol. 14: 233–58. doi:10.1146/annurev.immunol.14.1.233. PMID 8717514.
• Greenfield EA, Nguyen KA, Kuchroo VK (1998). "CD28/B7 costimulation: a review". Crit. Rev. Immunol. 18 (5): 389–418. doi:10.1615/critrevimmunol.v18.i5.10. PMID 9784967.
• Chang TT, Kuchroo VK, Sharpe AH (2002). "Role of the B7-CD28/CTLA-4 pathway in autoimmune disease". Signal Transduction Pathways in Autoimmunity. Current Directions in Autoimmunity. Vol. 5. pp. 113–30. doi:10.1159/000060550. ISBN 978-3-8055-7308-5. PMID 11826754. {{cite book}}: |journal= ignored (help)
• Bour-Jordan H, Blueston JA (2002). "CD28 function: a balance of costimulatory and regulatory signals". J. Clin. Immunol. 22 (1): 1–7. doi:10.1023/A:1014256417651. PMID 11958588. S2CID 38060684.
• Greenway AL, Holloway G, McPhee DA, Ellis P, Cornall A, Lidman M (2004). "HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication". J. Biosci. 28 (3): 323–35. doi:10.1007/BF02970151. PMID 12734410. S2CID 33749514.
• Bénichou S, Benmerah A (2003). "[The HIV nef and the Kaposi-sarcoma-associated virus K3/K5 proteins: "parasites"of the endocytosis pathway]". Med Sci (Paris). 19 (1): 100–6. doi:10.1051/medsci/2003191100. PMID 12836198.
• Tolstrup M, Ostergaard L, Laursen AL, Pedersen SF, Duch M (2004). "HIV/SIV escape from immune surveillance: focus on Nef". Curr. HIV Res. 2 (2): 141–51. doi:10.2174/1570162043484924. PMID 15078178.
• Anderson JL, Hope TJ (2005). "HIV accessory proteins and surviving the host cell". Current HIV/AIDS Reports. 1 (1): 47–53. doi:10.1007/s11904-004-0007-x. PMID 16091223. S2CID 34731265.
• Li L, Li HS, Pauza CD, Bukrinsky M, Zhao RY (2006). "Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions". Cell Res. 15 (11–12): 923–34. doi:10.1038/sj.cr.7290370. PMID 16354571. S2CID 24253878.
• Stove V, Verhasselt B (2006). "Modelling thymic HIV-1 Nef effects". Curr. HIV Res. 4 (1): 57–64. doi:10.2174/157016206775197583. PMID 16454711.

External links

• Mouse CD Antigen Chart
• Human CD Antigen Chart
• Human CD28 genome location and CD28 gene details page in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: P10747 (T-cell-specific surface glycoprotein CD28) at the PDBe-KB.