|Molecule Type||Antigen Expression||Molecular Weight|
Min / Max
|Lineage Restricted Molecule|
Type 1 glycoprotein
|44 / 44|
90 / 90
|CD28 is expressed on most T lineage cells with the exception of a small subset CD8+ cells. Expression is in plasma cells and mature CD3+ thymocytes have higher levels of CD28 than the immature cells. There are high levels on most peripheral T lymphocytes, all CD4+ cells and ~50% of human CD8+ cells are positive. In general, activation of T cells leads to enhanced CD28 expression but ligation of CD28 leads to its transient downregulation. |
|MOLECULAR FAMILY NAME: Belongs to the immunoglobulin supergene family.|
CD28 is a single-pass type-1 disulfide-linked homodimeric 202 aa glycoprotein. It contains an 134 aa extracellular domain which contains an Ig-likeV-type domain and 5 potential N-linked glycosylation sites, a 27 aa transmembrane domain and a 41 aa cytoplasmic domain containing a tyrosine-containing motif. The extracellular domain shares a significant amino acid sequence homology with CD152 (CTLA-4), with a 31% identity. The 2 genes are less than 150 kb apart, suggesting that they share a common ancestor in evolution and bind the same ligands.
There are 4 transcripts with 1.3 kb, 1.5 kb, 3.5 kb, and 3.7 kb are observed in T cells. The longer pair of transcripts with 3.5/3.7 kb is generated by the use of an alternative polyadenylation signal. The size difference between the 1.3 kb and 1.5 kb arise from alternative splicing within exon 2 extracellular domain.
There are 5 potential N-linked glycosylation sites.
|Like CD152, CD28 binds both CD80 and CD86 using a highly conserved motif MYPPPY in the CDR3-like loop. CD28 binds CD80 with a low affinity of kDa 4 mM and dissociates very rapidly of K off >1.6s-1. Binding to CD86 may be even weaker. The cytoplasmic domain interacts with phosphatidylinositol 3-kinase (PI-3k), the complex between GRB-2 and the guanine nucleotide exchange protein SOS (GRB-2/SOS), and the tyrosine kinase ITK. SH2 domains in PI-3k and GRB-2/SOS mediate binding to the CD28 motif YMNMT, after it has been phosphorylated by Lck and Fyn.|
LIGANDS AND MOLECULES ASSOCIATED WITH CD28
|CD28 is considered a major co-stimulatory molecule, inducing T lymphocyte activation and IL-2 synthesis and preventing cell death. Studies in vitro indicate that CD28 is the ligand on T cells by CD80 (B7-1) and CD86 (B7-2) on antigen presenting cells provides a co-stimulatory signal required for T cell activation but blocking this interaction causes functional inactivation of T cells. CD28 costimulation is essential for CD4-positive T-cell proliferation, survival, IL-2 production and T-helper type-2 development. Knockout mice lacking CD28 are able to mount effective T cell responses and are mainly defective in T cell-dependent antibody responses, suggesting that CD28 is mainly important for T and B cell interactions and humoral immunity. The cytoplasmic domain binds intracellular signaling molecules |
PI 3-kinase, guanine nucleotide exchange protein (GRB-2-SOS) via the PYMNM motif and binds tyrosine kinase ITK. The motif requires phosphorylation by Lck and Fyn. Intact CD28 antibodies co-stimulate T cell proliferation and cytokine production with the presence of suboptimal amount of PHA, PMA, CD3 mAbs or CD2 mAbs.
BIOCHEMICAL ACTIVITY: No information.
DISEASE RELEVANCE AND FUNCTION OF CD28 IN INTACT ANIMAL
The blockade of CD28 signal, using mAbs against CD80 and/or CD86 or CD152 Ig fusion protein, induces a functional inactivation of T cells in a number of in vivo experimental disease models. CD28 deficient mice have normal T cell development and normal cell mediated immunity but T cell mediated humoral immunity was significantly reduced.
|MOLECULAR INTERACTIONS -|
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD28: No information.
SUBSTRATES: No information.
ENZYMES WHICH MODIFY CD28: No information.
A key challenge will be elucidation of the cellular and molecular mechanism which distinquish the function of CTL-4 from that of CD28 with which CTLA-4 shares aa sequence homology and common ligands, CD80/CD86.
Database accession numbers
Revised June 25, 2008