CD28

CD28 molecule
Structure of human CD28.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1YJD, 3WA4
Identifiers
Symbols	CD28 ; Tp44
External IDs	OMIM: 186760 MGI: 88327 HomoloGene: 4473 ChEMBL: 5191 GeneCards: CD28 Gene
Gene ontology Molecular function • protease binding • SH3/SH2 adaptor activity • protein binding • coreceptor activity • protein kinase binding • identical protein binding Cellular component • immunological synapse • cytosol • plasma membrane • integral component of plasma membrane • external side of plasma membrane Biological process • positive regulation of inflammatory response to antigenic stimulus • humoral immune response • cell surface receptor signaling pathway • epidermal growth factor receptor signaling pathway • fibroblast growth factor receptor signaling pathway • positive regulation of gene expression • negative regulation of gene expression • positive regulation of phosphatidylinositol 3-kinase signaling • viral process • T cell costimulation • Fc-epsilon receptor signaling pathway • cytokine biosynthetic process • positive regulation of T cell proliferation • negative thymic T cell selection • regulatory T cell differentiation • positive regulation of viral genome replication • positive regulation of interleukin-2 biosynthetic process • innate immune response • regulation of regulatory T cell differentiation • positive regulation of translation • positive regulation of mitotic nuclear division • positive regulation of transcription from RNA polymerase II promoter • positive regulation of alpha-beta T cell proliferation • neurotrophin TRK receptor signaling pathway • phosphatidylinositol-mediated signaling • positive regulation of isotype switching to IgG isotypes • regulation of defense response to virus by virus • T cell receptor signaling pathway • positive regulation of protein kinase B signaling • apoptotic signaling pathway Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	940	12487
Ensembl	ENSG00000178562	ENSMUSG00000026012
UniProt	P10747	P31041
RefSeq (mRNA)	NM_001243077	NM_007642
RefSeq (protein)	NP_001230006	NP_031668
Location (UCSC)	Chr 2: 203.71 – 203.74 Mb	Chr 1: 60.72 – 60.77 Mb
PubMed search	[1]	[2]

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.

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.

As a drug target

The drug TGN1412, which was produced by the German biotech company TeGenero and which 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.

Interactions

CD28 has been shown to interact with:

• GRAP2,
• Grb2, and
• PIK3R1.

See also

• List of human clusters of differentiation

External links

• Mouse CD Antigen Chart
• Human CD Antigen Chart