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34-440: 1493 12477 ENSG00000163599 ENSMUSG00000026011 P16410 P09793 NM_001037631 NM_005214 NM_001281976 NM_009843 NP_001032720 NP_005205 NP_001268905 NP_033973 Cytotoxic T-lymphocyte associated protein 4 , (CTLA-4) also known as CD152 ( cluster of differentiation 152), is a protein receptor that functions as an immune checkpoint and downregulates immune responses . CTLA-4

68-410: A chemokine receptor on the surface of a T helper cell to gain entry. The number of CD4 and CD8 T cells in blood is often used to monitor the progression of HIV infection . While CD molecules are very useful in defining leukocytes, they are not merely markers on the cell surface . Though only a fraction of known CD molecules have been thoroughly characterised, most of them have important functions. In

102-641: 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

136-578: A stem cell , as opposed to a fully differentiated endothelial cell . Some cell populations can also be defined as , , or (alternatively, , , or ), indicating an overall variability in CD expression , particularly when compared to other cells being studied. A review of the development of T cells in the thymus uses this nomenclature to identify cells transitioning from CD4 /CD8 double-positive cells to CD4 /CD8 . Since 1982 there have been nine Human Leukocyte Differentiation Antigen Workshops culminating in

170-663: A collaboration between the groups of Dr. Gulbu Uzel, Dr. Steven Holland, and Dr. Michael Lenardo from the National Institute of Allergy and Infectious Disease , Dr. Thomas Fleisher from the NIH Clinical Center at the National Institutes of Health , and their collaborators in 2014. In the same year a collaboration between the groups of Dr. Bodo Grimbacher, Dr. Shimon Sakaguchi, Dr. Lucy Walker and Dr. David Sansom and their collaborators described

204-426: A conference. The CD system is commonly used as cell markers in immunophenotyping , allowing cells to be defined based on what molecules are present on their surface. These markers are often used to associate cells with certain immune functions . While using one CD molecule to define populations is uncommon (though a few examples exist), combining markers has allowed for cell types with very specific definitions within

238-418: A diagnosis is made, the treatment is based on an individual’s clinical condition and may include standard management for autoimmunity and immunoglobulin deficiencies. A study reported in 2016 treated a Korean CHAI disease patient with abatacept , which is a fusion protein of CTLA-4 and an antibody, and was able to control immune activity and improve patient symptoms. Regular administration of abatacept improved

272-581: A means of inhibiting immune system tolerance to tumours and thereby providing a potentially useful immunotherapy strategy for patients with cancer). This therapy was the first approved immune checkpoint blockade therapy. Another is tremelimumab . The 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation". CTLA-4 has been shown to interact with: This article incorporates text from

306-432: A number of organs, including the gut, lungs, bone marrow, central nervous system and kidneys. Most patients have diarrhea or enteropathy . Lymphadenopathy and hepatosplenomegaly are also common, as is autoimmunity. The organs affected by autoimmunity vary but include thrombocytopenia , hemolytic anemia , thyroiditis , type I diabetes, psoriasis , and arthritis . Respiratory infections are also common. Importantly,

340-755: A pivotal role. CTLA-4 may also function via modulation of cell motility and/or signaling through PI3 kinase. Early multiphoton microscopy studies observing T-cell motility in intact lymph nodes appeared to give evidence for the so-called ‘reverse-stop signaling model’. In this model CTLA-4 reverses the TCR-induced ‘stop signal’ needed for firm contact between T cells and antigen-presenting cells (APCs). However, those studies compared CTLA-4 positive cells, which are predominantly regulatory cells and are at least partially activated, with CTLA-4 negative naive T cells. The disparity of these cells in multiple regards may explain some of these results. Other groups who have analyzed

374-432: A second receptor for the T cell costimulation ligand B7 . In November 1995, the labs of Tak Wah Mak and Arlene Sharpe independently published their findings on the discovery of the function of CTLA-4 as a negative regulator of T-cell activation, by knocking out the gene in mice. Previous studies from several labs had used methods which could not definitively define the function of CTLA-4, and were contradictory. CTLA-4

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408-531: A similar phenotype. CTLA-4 mutations are inherited in an autosomal dominant manner. This means a person only needs one abnormal gene from one parent. The one normal copy is not enough to compensate for the one abnormal copy. Dominant inheritance means most families with CTLA-4 mutations have affected relatives in each generation on the side of the family with the mutation . Symptomatic patients with CTLA-4 mutations are characterized by an immune dysregulation syndrome including extensive T cell infiltration in

442-413: A stimulatory signal. CTLA-4 is also found in regulatory T cells (Tregs) and contributes to their inhibitory function. T cell activation through the T cell receptor and CD28 leads to increased expression of CTLA-4. The mechanism by which CTLA-4 acts in T cells remains somewhat controversial. Biochemical evidence suggested that CTLA-4 recruits a phosphatase to the T cell receptor (TCR), thus attenuating

476-456: Is a list of definitions of fundamental terms and concepts used in biology , the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions from sub-disciplines and related fields, see Glossary of cell biology , Glossary of genetics , Glossary of evolutionary biology , Glossary of ecology , Glossary of environmental science and Glossary of scientific naming , or any of

510-569: Is a member of the immunoglobulin superfamily that is expressed by activated T cells and transmits an inhibitory signal to T cells . CTLA-4 is homologous to the T-cell co-stimulatory protein, CD28 , and both molecules bind to CD80 and CD86 , also called B7-1 and B7-2 respectively, on antigen-presenting cells. CTLA-4 binds CD80 and CD86 with greater affinity and avidity than CD28 thus enabling it to outcompete CD28 for its ligands. CTLA-4 transmits an inhibitory signal to T cells, whereas CD28 transmits

544-479: Is constitutively expressed in regulatory T cells but only upregulated in conventional T cells after activation – a phenomenon which is particularly notable in cancers. It acts as an "off" switch when bound to CD80 or CD86 on the surface of antigen-presenting cells . It is encoded by the gene CTLA4 in humans. The CTLA-4 protein is encoded by the Ctla-4 gene in mice. CTLA-4 was first identified in 1991 as

578-612: 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. Germline haploinsufficiency of CTLA-4 leads to CTLA-4 deficiency or CHAI disease (CTLA4 haploinsufficiency with autoimmune infiltration), a rare genetic disorder of the immune system. This may cause a dysregulation of the immune system and may result in lymphoproliferation, autoimmunity, hypogammaglobulinemia , recurrent infections, and may slightly increase one’s risk of lymphoma . CTLA-4 mutations have first been described by

612-522: Is said to be incomplete when some individuals fail to express the trait and seem completely asymptomatic, even though they carry the allele. The penetrance is estimated to be about 60%. The clinical symptoms are caused by abnormalities of the immune system. Most patients develop reduced levels of at least one immunoglobulin isotype, and have low CTLA-4 protein expression in T regulatory cells, hyperactivation of effector T cells, low switched memory B cells , and progressive loss of circulating B cells. Once

646-627: The Krebs cycle and tricarboxylic acid cycle (TCA) . Also called the macula adhaerens . Also called a trophic pyramid , eltonian pyramid , energy pyramid , or sometimes food pyramid . Sometimes called an ecospecies . Also called a nonspontaneous reaction or unfavorable reaction . Also called symbiogenesis . Also spelled foetus . (pl.) flagella (pl.) foramimina Also called an exotic species , foreign species , alien species , non-native species , or non-indigenous species . Also called

680-604: The United States National Library of Medicine , which is in the public domain . Cluster of differentiation The cluster of differentiation (also known as cluster of designation or classification determinant and often abbreviated as CD ) is a protocol used for the identification and investigation of cell surface molecules providing targets for immunophenotyping of cells. In terms of physiology, CD molecules can act in numerous ways, often acting as receptors or ligands important to

714-474: The Treg cell adhesion zone. Although it is reversible upon T regulatory cell disengagement, this sequestration of essential cytoskeletal components causes a lethargic state of DCs, leading to reduced T cell priming. This suggests Treg-mediated immune suppression is a multi-step process. In addition to CTLA-4 CD80/CD86 interaction, fascin-dependent polarization of the cytoskeleton towards DC-Treg immune synapse may play

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748-536: The cell. A signal cascade is usually initiated, altering the behavior of the cell (see cell signaling ). Some CD proteins do not play a role in cell signaling, but have other functions, such as cell adhesion . CD for humans is numbered up to 371 (as of 21 April 2016 ). The CD nomenclature was proposed and established in the 1st International Workshop and Conference on Human Leukocyte Differentiation Antigens (HLDA), held in Paris in 1982. This system

782-434: The clinical presentations and disease courses are variable with some individuals severely affected, whereas others show little manifestation of disease. This “ variable expressivity ,” even within the same family, can be striking and may be explained by differences in lifestyle, exposure to pathogens, treatment efficacy, or other genetic modifiers. This condition is described to have incomplete penetrance of disease. Penetrance

816-426: The designation (e.g., CD2 molecule). Currently, "CD2" is generally used to designate the molecule, and "CD2 antibody " is used to designate the antibody. Cell populations are usually defined using a '+' or a '−' symbol to indicate whether a certain cell fraction expresses or lacks a CD molecule. For example, a " CD34 +, CD31 −" cell is one that expresses CD34 but not CD31. This CD combination typically corresponds to

850-479: The effect of antibodies to CTLA-4 in vivo have concluded little or no effect upon motility in the context of anergic T-cells. Antibodies to CTLA-4 may exert additional effects when used in vivo, by binding and thereby depleting regulatory T cells. The protein contains an extracellular V domain , a transmembrane domain, and a cytoplasmic tail. Alternate splice variants , encoding different isoforms , have been characterized. The membrane-bound isoform functions as

884-439: The example of CD4 and CD8, these molecules are critical in antigen recognition. Others (e.g., CD135 ) act as cell surface receptors for growth factors . Recently, the marker CD47 was found to have anti- phagocytic signals to macrophages and inhibit natural killer (NK) cells. This enabled researchers to apply CD47 as a potential target to attenuate immune rejection . Extracellular This glossary of biology terms

918-509: The immune system. CD molecules are utilized in cell sorting using various methods, including flow cytometry . Two commonly used CD molecules are CD4 and CD8 , which are, in general, used as markers for helper and cytotoxic T cells, respectively. These molecules are defined in combination with CD3+, as some other leukocytes also express these CD molecules (some macrophages express low levels of CD4; dendritic cells express high levels of CD8). Human immunodeficiency virus binds CD4 and

952-555: The importance and results of this interaction are uncertain. Variants in this gene have been associated with Type 1 diabetes , Graves' disease , Hashimoto's thyroiditis , celiac disease , systemic lupus erythematosus , thyroid-associated orbitopathy, primary biliary cirrhosis and other autoimmune diseases . Polymorphisms of the CTLA-4 gene are associated with autoimmune diseases such as rheumatoid arthritis , autoimmune thyroid disease and multiple sclerosis, though this association

986-409: The molecule. If the molecule has not been well characterized or has only one mAb, it is usually given the provisional indicator "w" (as in " CDw186 "). For instance, CD2 mAbs are reagents that react with a 50‐kDa transmembrane glycoprotein expressed on T cells . The CD designations were used to describe the recognized molecules but had to be clarified by attaching the term antigen or molecule to

1020-513: The organism-specific glossaries in Category:Glossaries of biology . Also called an antibacterial . Also called selective breeding . Sometimes used interchangeably with primary producer . Also called the biosynthetic phase , light-independent reactions , dark reactions , or photosynthetic carbon reduction (PCR) cycle . Also called carbon assimilation . Also called cytology . Also called

1054-541: The patient’s severe anemia and diarrhea (3L/day) and brought 3-year-long hospitalization to an end. The comparatively higher binding affinity of CTLA-4 than that of CD28 has made CTLA-4 a potential therapy for autoimmune diseases . Fusion proteins of CTLA-4 and antibodies (CTLA4-Ig) have been used in clinical trials for rheumatoid arthritis. The fusion protein CTLA4-Ig is commercially available as Orencia ( abatacept ). A second generation form of CTLA4-Ig known as belatacept

Cytotoxic T-lymphocyte associated protein 4 - Misplaced Pages Continue

1088-569: The signal. This work remains unconfirmed in the literature since its first publication. More recent work has suggested that CTLA-4 may function in vivo by capturing and removing CD80 and CD86 from the membranes of antigen-presenting cells, thus making these unavailable for triggering of CD28. In addition to that, it has been found that dendritic cell (DC) - Treg interaction causes sequestration of Fascin-1 , an actin-bundling protein essential for immunological synapse formation and skews Fascin-1–dependent actin polarization in antigen presenting DCs toward

1122-461: Was intended for the classification of the many monoclonal antibodies (mAbs) generated by different laboratories around the world against epitopes on the surface molecules of leukocytes (white blood cells). Since then, its use has expanded to many other cell types, and more than 370 CD unique clusters and subclusters have been identified. The proposed surface molecule is assigned a CD number once two specific monoclonal antibodies are shown to bind to

1156-555: 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 Trial) study. It was approved for renal transplantation in patients that are sensitized to Epstein–Barr virus (EBV). Conversely, there is increasing interest in the possible therapeutic benefits of blocking CTLA-4 (using antagonistic antibodies against CTLA such as ipilimumab —FDA approved for melanoma in 2011—as

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