|CD152||CTLA-4 (cytotoxic T lymphocyte-associated protein 4)|
|Molecule Type||Antigen Expression||Molecular Weight|
Min / Max
|Lineage Restricted Molecule|
Type 1 glycoprotein
|33 / 33|
50 / 50
|CD152 is expressed on the cell surface by activated T cells only with the exception if regulatory CD4+CD25+ T cells that appear to constitutively express CD152 but not on resting T lymphocytes. Expression peaks at ~24 hours and then subsides by 72 hours, but is always 30-50-fold lower than CD28. CD28 ligation is particularly effective in inducing CD152 expression. CD152 mRNA is frequently present in the absence of the cell surface CD152 protein, suggesting post-transcriptional regulation of cell surface. Expression occurs in some activated B cells. There is wide expression with the highest levels in lymphoid tissues. Frequency of expression varies more with Th2 cells expressing CD152 than Th1.|
|MOLECULAR FAMILY NAME: Belongs the immunoglobulin gene superfamily.|
CD152 is a single-pass type-1 223 aa glycoprotein. It contains a ~37 aa leader sequence which is cleaved during biosynthesis, an 124 aa extracellular domain which contains an Ig-like V-type domain and a 2 potential glycosylation sites, a 26 aa transmembrane domain and a 36 aa cytoplasmic domain which contains a PI3K motif and a tyrosine-containing motif (YVKM) that targets CD152 to Golgi or post-Golgi intracellular membranes. The cytoplasmic domain is encoded by 4 exons and containing 2 potential phosphorylation sites. The extracellular domain shares significant aa sequence homology with CD28 and is expressed as a disulfide-linked homodimer interconnected by a disulfide bond ay Cys120.
Alternative splicing yields 2 different isoforms which have alternative polyadenylation sites. The membrane-bound form functions as a homodimer interconnected by a disulfied bond, while the soluble isoform functions as a monomer. The longer isoform contains a repeated - AU - motif. The number of these AU repeats varies between different individuals, leading to a restriction fragment length polymorphism (RFLP) which has been linked to various autoimmune diseases.
The extracellular region has 2 potential N-linked glycosylation sites. The cytoplasmic region of this molecule contains a tyrosine-containing motif which localizes this molecule primarily to Golgi- or post-Golgi intracellular membranes.
Like CD28, CD152 binds both CD80 and CD86. The binding site for CD80 includes a highly conserved motif MYPPPY in the CDR3-like loop. CD80 and CD86 bind CD152 with kDas of 0.4 and 2.2 mM, respectively and dissociate rapidly K off >0.4s-1. The CD152 cytoplasmic domain has been reported to interact with the SH2 domain of the tyrosine phosphatase, SHP-2, PTP1D, and SYP, through the phosphotyrosine motif PYVKM. An association with phosphatidylinositol 3-kinase(PI-3 kinase) has also been reported, apparently through the same motif.
|CD152 is the inducible receptor for CD80 and CD86, transported from intracellular vesicles to the cell membrane at the immunological synapse after cell activation. Despite being a homologue of CD28 abd binding the same ligands, CD152 antagonizes some functions of CD28 and has an inhibitory effect on T-cell functions. Unlike CD28, CD152 downregulates IL-2 production and inhibits cell-cycle progression in T cells, thereby depressing T-cell proliferation. In activated Th2 cells, CD152 mediates anti-apoptotic signaling via PI-3K in a Fas/Fas ligand dependent manner. It is thought that the interaction of CF152+ T cells with CD80 and CD86 on dendritic cells results in the activation of indoleamine 2,3-dioxygenase (IDO), which metabolizes tryptophan. As reduced levels of free tryptophan are associated with decreased T-cell activation, this may represent another mechanism of suppression of T-cell function. The prevailing current view is that this stimulation results from blocking of CD152/CD80/CD86 interactions which downregulates T cell activation. Intact anti-CD152 mAbs stimulate T cell proliferation in a number of in vitro and in vivo systems. CD152 is a receptor for CD80/CD86 and may be associated with cytotoxic T lymphocytes. |
BIOCHEMICAL ACTIVITY: No information.
DISEASE RELEVANCE AND FUNCTION OF CD152 IN INTACT ANIMAL
The genetic linkage with human autoimmune disorders suggests that CD152 may play a role in human disease. Defects in CD152 have been associated with insulin-dependent type 1 diabetes mellitus, Graves disease, Hashimoto thyroiditis, Addison's disease, multiple sclerosis, celiac disease, systemic lupus erythematosus, thyroid-associated orbitopathy and other autoimmune diseases. In an experimental model of autoimmune enchephalomyelitis, antibody to CD152 increased the severity of the disease. CD152-deficient mice display a severe lymphoproliferative disorder, and die a few months after birth. .
|MOLECULAR INTERACTIONS -|
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD152
SUBSTRATES: No information.
ENZYMES WHICH MODIFY CD152: No information.
Database accession numbers
Revised June 25, 2008