CD152 CTLA-4 (cytotoxic T lymphocyte-associated protein 4)
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Lineage Restricted Molecule
Type 1 glycoprotein
T Cell
B Cell
Lymphoid Cell
33 / 33
50 / 50

Expression
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.



Structure
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.
 
MOLECULAR MASS
Cell Type Unreduced Reduced Comment
COS ~46 kDa ~30 kDa
Activated peripheral blood (PBL) ~50 kDa ~33 kDa

POST-TRANSCRIPTIONAL MODIFICATION

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.

POST-TRANSLATIONAL MODIFICATION

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.

Ligands

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.

LIGANDS AND MOLECULES ASSOCIATED WITH CD152
Molecule Comment
CD80 (ligand for CD28) CD152 (CTLA-4) is a high avidity receptor for CD80
CD86 (ligand for CD28) CD152 (CTLA-4) is a high avidity receptor for CD86
Phosphatidylinositol 3-kinase (PI 3-kinase) The cytoplasmic region of CD152 (CTLA-4) contains the motif-YVKM- which binds PI 3-kinase
Protein tyrosine phosphatase 1D (PTP1D) Association of CD152 (CTLA-4) with PTP1D has been reported

  



Function
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. .

Comments
MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD152
Molecule Comment
AP-1 These elements have been identified in genomic sequence upstream of the murine CTLA-4 gene
CD28re These elements have been identified in genomic sequence upstream of the murine CTLA-4 gene
IL-2kb These elements have been identified in genomic sequence upstream of the murine CTLA-4 gene
OCT-1 These elements have been identified in genomic sequence upstream of the murine CTLA-4 gene

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD152: No information.


Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 1493P16410
MouseA29063P09793X05719
Antibodies
BN13   View Reactivity
BNI3.1   View Reactivity

Revised June 25, 2008


Contact us: Webmaster |  509-335-9515 | Accessibility | Copyright | Policies
College of Veterinary Medicine Washington State University, Pullman, WA, 99164-7010 USA
Copyright 1995-2003 Washington State University