CTLA-4
Encyclopedia
CTLA4 also known as CD152 (Cluster of differentiation
152) is a protein
that plays an important regulatory role in the immune system
. In humans, the CTLA4 protein is encoded by the CTLA4 gene
.
s. CTLA4 is similar to the T-cell costimulatory protein CD28
, and both molecules bind to CD80
and CD86
(also called B7) on antigen-presenting cells. CTLA4 transmits an inhibitory signal to T cells, whereas CD28 transmits a stimulatory signal.
Intracellular CTLA4 is also found in regulatory T cells and may be important to their function. T cell activation through the T cell receptor and CD28 leads to increased expression of CTLA-4, an inhibitory receptor for B7 molecules (i.e. CD80 and CD86).
Multiphoton microscopy studies observing T-cell motility in intact lymph nodes gave evidence for the so called ‘reverse-stop signaling model’. In this model CTLA 4 reverse the classic TCR-induced ‘stop signal’ needed for firm contact between T cells and antigen-presenting cells (APCs).
V domain
, a transmembrane
domain, and a cytoplasm
ic tail. Alternate splice variants
, encoding different isoform
s, have been characterized. The membrane-bound isoform functions as a homodimer interconnected by a disulfide bond, while the soluble isoform functions as a monomer. The intracellular domain is similar to that of CD28
, in that it has no intrinsic catalytic activity and contains one YVKM motif able to bind PI3K
, PP2A
and SHP-2
and one proline-rich motif able to bind SH3
containing proteins. The first role of CTLA-4 in inhibiting T cell responses seem to be directly via SHP-2 and PP2A dephosphorylation of TCR-proximal signalling proteins such as CD3 and LAT
. CTLA-4 can also affect signalling indirectly via competing with CD28 for CD80/86 binding. CTLA-4 can also bind PI3K, although the importance and results of this interaction are uncertain.
, Graves' disease
, Hashimoto's thyroiditis
, celiac disease
, systemic lupus erythematosus
, thyroid-associated orbitopathy, primary biliary cirrhosis
and other autoimmune disease
s.
Polymorphisms of the CTLA-4 gene are associated with autoimmune diseases such as autoimmune thyroid disease and multiple sclerosis, though this association is often weak. In Systemic Lupus Erythematosus (SLE), the splice variant sCTLA-4 is found to be aberrantly produced and found in the serum of patients with active SLE.
). A second generation form of CTLA4-Ig known as belatacept
was recently approved by the FDA based on favorable results from the randomized Phase III BENEFIT (Belatacept Evaluation of Nephroprotection and Efficacy as First Line Immunosuppression) study. It was approved for renal transplantation in patients that are sensitized to EBV, or Ebstein Barr Virus.
) as a means of inhibiting immune system tolerance to tumours and thereby providing a potentially useful immunotherapy strategy for patients with cancer.
with CD80
, AP2M1
and PPP2R5A
.
Cluster of differentiation
The cluster of differentiation is a protocol used for the identification and investigation of cell surface molecules present on white blood cells, providing targets for immunophenotyping of cells...
152) is a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that plays an important regulatory role in the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. In humans, the CTLA4 protein is encoded by the CTLA4 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Function and mechanism
CTLA4 is a member of the immunoglobulin superfamily, which is expressed on the surface of Helper T cells and transmits an inhibitory signal to T cellT cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s. CTLA4 is similar to the T-cell costimulatory protein CD28
CD28
CD28 is one of the molecules expressed on T cells that provide co-stimulatory signals, which are required for T cell activation. CD28 is the receptor for CD80 and CD86 . When activated by Toll-like receptor ligands, the CD80 expression is upregulated in antigen presenting cells...
, and both molecules bind to CD80
CD80
Cluster of Differentiation 80 is a protein found on activated B cells and monocytes that provides a costimulatory signal necessary for T cell activation and survival...
and CD86
CD86
Cluster of Differentiation 86 is a protein expressed on antigen-presenting cells that provides costimulatory signals necessary for T cell activation and survival...
(also called B7) on antigen-presenting cells. CTLA4 transmits an inhibitory signal to T cells, whereas CD28 transmits a stimulatory signal.
Intracellular CTLA4 is also found in regulatory T cells and may be important to their function. T cell activation through the T cell receptor and CD28 leads to increased expression of CTLA-4, an inhibitory receptor for B7 molecules (i.e. CD80 and CD86).
Multiphoton microscopy studies observing T-cell motility in intact lymph nodes gave evidence for the so called ‘reverse-stop signaling model’. In this model CTLA 4 reverse the classic TCR-induced ‘stop signal’ needed for firm contact between T cells and antigen-presenting cells (APCs).
Structure
The protein contains an extracellularExtracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
V domain
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
, a transmembrane
Transmembrane protein
A transmembrane protein is a protein that goes from one side of a membrane through to the other side of the membrane. Many TPs function as gateways or "loading docks" to deny or permit the transport of specific substances across the biological membrane, to get into the cell, or out of the cell as...
domain, and a cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
ic tail. Alternate splice variants
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
, encoding different isoform
Protein isoform
A protein isoform is any of several different forms of the same protein. Different forms of a protein may be produced from related genes, or may arise from the same gene by alternative splicing. A large number of isoforms are caused by single-nucleotide polymorphisms or SNPs, small genetic...
s, have been characterized. The membrane-bound isoform functions as a homodimer interconnected by a disulfide bond, while the soluble isoform functions as a monomer. The intracellular domain is similar to that of CD28
CD28
CD28 is one of the molecules expressed on T cells that provide co-stimulatory signals, which are required for T cell activation. CD28 is the receptor for CD80 and CD86 . When activated by Toll-like receptor ligands, the CD80 expression is upregulated in antigen presenting cells...
, in that it has no intrinsic catalytic activity and contains one YVKM motif able to bind PI3K
Phosphoinositide 3-kinase
Phosphatidylinositol 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing...
, PP2A
Protein Phosphatase 2
Protein phosphatase 2 , also known as PP2A, is an enzyme that in humans is encoded by the PPP2CA gene. The PP2A heterotrimeric protein phosphatase, is a ubiquitous and conserved Serine/Threonine phosphatase with broad substrate specificity and diverse cellular functions...
and SHP-2
PTPN11
Tyrosine-protein phosphatase non-receptor type 11 also known as protein-tyrosine phosphatase 1D or protein-tyrosine phosphatase 2C is an enzyme that in humans is encoded by the PTPN11 gene. PTPN11 is a protein tyrosine phosphatase Shp2.PTPN11 is a member of the protein tyrosine phosphatase ...
and one proline-rich motif able to bind SH3
SH3 domain
The SRC Homology 3 Domain is a small protein domain of about 60 amino acids residues first identified as a conserved sequence in the viral adaptor protein v-Crk and the non-catalytic parts of enzymes such as phospholipase and several cytoplasmic tyrosine kinases such as Abl and Src...
containing proteins. The first role of CTLA-4 in inhibiting T cell responses seem to be directly via SHP-2 and PP2A dephosphorylation of TCR-proximal signalling proteins such as CD3 and LAT
Linker of activated T cells
Linker of Activated T cells, also known as LAT, is a protein which in humans is encoded by the LAT gene. Alternative splicing results in multiple transcript variants encoding different isoforms.-Function:...
. CTLA-4 can also affect signalling indirectly via competing with CD28 for CD80/86 binding. CTLA-4 can also bind PI3K, although the importance and results of this interaction are uncertain.
Clinical significance
Mutations in this gene have been associated with insulin-dependent diabetes mellitusDiabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
, Graves' disease
Graves' disease
Graves' disease is an autoimmune disease where the thyroid is overactive, producing an excessive amount of thyroid hormones...
, Hashimoto's thyroiditis
Hashimoto's thyroiditis
Hashimoto's thyroiditis or chronic lymphocytic thyroiditis is an autoimmune disease in which the thyroid gland is gradually destroyed by a variety of cell- and antibody-mediated immune processes. It was the first disease to be recognized as an autoimmune disease...
, celiac disease
Coeliac disease
Coeliac disease , is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward...
, systemic lupus erythematosus
Systemic lupus erythematosus
Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...
, thyroid-associated orbitopathy, primary biliary cirrhosis
Primary biliary cirrhosis
Primary biliary cirrhosis, often abbreviated PBC, is an autoimmune disease of the liver marked by the slow progressive destruction of the small bile ducts within the liver. When these ducts are damaged, bile builds up in the liver and over time damages the tissue. This can lead to scarring,...
and other autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
s.
Polymorphisms of the CTLA-4 gene are associated with autoimmune diseases such as autoimmune thyroid disease and multiple sclerosis, though this association is often weak. In Systemic Lupus Erythematosus (SLE), the splice variant sCTLA-4 is found to be aberrantly produced and found in the serum of patients with active SLE.
Agonists to reduce immune activity
The comparatively higher binding affinity of CTLA4 has made it a potential therapy for autoimmune diseases. It plays a role in the initial immune response to and infection of immune cells by HIV, along with the PD-1 pathway and others. Fusion proteins of CTLA4 and antibodies (CTLA4-Ig) have been used in clinical trials for rheumatoid arthritis. The fusion protein CTLA4-Ig is commercially available as Orencia (abataceptAbatacept
Abatacept is a fusion protein composed of an immunoglobulin fused to the extracellular domain of CTLA-4, a molecule capable of binding B7. Abatacept is a selective costimulation modulator as it inhibits the costimulation of T cells...
). A second generation form of CTLA4-Ig known as belatacept
Belatacept
Belatacept is a fusion protein composed of the Fc fragment of a human IgG1 immunoglobulin linked to the extracellular domain of CTLA-4, which is a molecule crucial for T-cell costimulation, selectively blocking the process of T-cell activation...
was recently approved by the FDA based on favorable results from the randomized Phase III BENEFIT (Belatacept Evaluation of Nephroprotection and Efficacy as First Line Immunosuppression) study. It was approved for renal transplantation in patients that are sensitized to EBV, or Ebstein Barr Virus.
Antagonists to increase immune activity
Conversely, there is increasing interest in the possible therapeutic benefits of blocking CTLA4 (using antibodies against CTLA such as ipilimumabIpilimumab
Ipilimumab , marketed as Yervoy, is a drug used for the treatment of melanoma, a type of skin cancer. It is a U.S...
) as a means of inhibiting immune system tolerance to tumours and thereby providing a potentially useful immunotherapy strategy for patients with cancer.
Interactions
CTLA-4 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with CD80
CD80
Cluster of Differentiation 80 is a protein found on activated B cells and monocytes that provides a costimulatory signal necessary for T cell activation and survival...
, AP2M1
AP2M1
AP-2 complex subunit mu is a protein that in humans is encoded by the AP2M1 gene.-Interactions:AP2M1 has been shown to interact with CTLA-4 and Alpha-1B adrenergic receptor.-Further reading:...
and PPP2R5A
PPP2R5A
Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform is an enzyme that in humans is encoded by the PPP2R5A gene.-Interactions:PPP2R5A has been shown to interact with PPP2R1B, PPP2R1A, CTLA-4, AXIN1 and PPP2CA....
.