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CTLA4 or CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), also known as CD152 (cluster of differentiation 152), is a protein receptor that, functioning as an immune checkpoint, (or checkpoint inhibitor), downregulates immune responses. CTLA4 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.
The CTLA-4 protein is encoded by the Ctla4 gene in mice and the CTLA4 gene in humans.
In 1987, cytotoxic T-lymphocyte antigen 4, or CTLA-4, was identified by Pierre Golstein and colleagues . In November 1995, the labs of Tak Wah Mak and Arlene H. 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.
CTLA4 is a member of the immunoglobulin superfamily that is expressed by activated T cells and transmits an inhibitory signal to T cells. CTLA4 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. CTLA4 transmits an inhibitory signal to T cells, whereas CD28 transmits a stimulatory signal. CTLA4 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 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 B7-1 and B7-2 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 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 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 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 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.
Variants in this gene have been associated with insulin-dependent diabetes mellitus, 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 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.
Germline haploinsufficiency of CTLA4 leads to CTLA4 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. CTLA4 mutations have first been described by 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 a similar phenotype.
CTLA4 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 CTLA4 mutations have affected relatives in each generation on the side of the family with the mutation.
Clinical and laboratory manifestations
Symptomatic patients with CTLA4 mutations are characterized by an immune dysregulation syndrome including extensive T cell infiltration in 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, 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 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 CTLA4 protein expression in T regulatory cells, hyperactivation of effector T cells, low switched memory B cells, and progressive loss of circulating B cells.
Once 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 recent study treated a Korean CHAI disease patient with CTLA4 mimetic, CTLA4-Ig (e.g.. abatacept) and was able to control immune activity and improve patient symptoms. Regular administration of abatacept improved the patient’s severe anemia and diarrhea (3L/day) and brought 3-year-long hospitalization to an end.
Agonists to reduce immune activity
The comparatively higher binding affinity of CTLA4 has made it a potential therapy for autoimmune diseases. 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 (abatacept). 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 Trial) study. It was approved for renal transplantation in patients that are sensitized to Epstein–Barr virus (EBV).
Antagonists to increase immune activity
Conversely, there is increasing interest in the possible therapeutic benefits of blocking CTLA4 (using antagonistic antibodies against CTLA such as ipilimumab (FDA approved for melanoma in 2011) as a means of inhibiting immune system tolerance to tumours and thereby providing a potentially useful immunotherapy strategy for patients with cancer. This is the first approved immune checkpoint blockade therapy. Another (not yet approved) 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:
- ↑ 1.0 1.1 1.2 Syn, Nicholas L; Teng, Michele W L; Mok, Tony S K; Soo, Ross A. "De-novo and acquired resistance to immune checkpoint targeting". The Lancet Oncology. 18 (12): e731–e741. doi:10.1016/s1470-2045(17)30607-1.
- ↑ 2.0 2.1 Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, Golstein P (1987). "A new member of the immunoglobulin superfamily--CTLA-4". Nature. 328 (6127): 267–70. doi:10.1038/328267a0. PMID 3496540.
- ↑ Dariavach P, Mattéi MG, Golstein P, Lefranc MP (December 1988). "Human Ig superfamily CTLA-4 gene: chromosomal localization and identity of protein sequence between murine and human CTLA-4 cytoplasmic domains". Eur. J. Immunol. 18 (12): 1901–5. doi:10.1002/eji.1830181206. PMID 3220103.
- ↑ 4.0 4.1 Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW (November 1995). "Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4". Science. 270 (5238): 985–8. doi:10.1126/science.270.5238.985. JSTOR 2888113. PMID 7481803.
- ↑ Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH (November 1995). "Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4" (PDF). Immunity. 3 (5): 541–7. doi:10.1016/1074-7613(95)90125-6. PMID 7584144.
- ↑ Pardoll, Drew M. (December 2012). "Immunology beats cancer: a blueprint for successful translation". Nature Immunology. 13 (12): 1129–1132. doi:10.1038/ni.2392. ISSN 1529-2916. PMC 4659410. PMID 23160205.
- ↑ Krummel MF, Allison JP (1995). "CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation". J. Exp. Med. 182 (2): 459–65. doi:10.1084/jem.182.2.459. PMC 2192127. PMID 7543139.
- ↑ Walunas TL, Bakker CY, Bluestone JA (1996). "CTLA-4 ligation blocks CD28-dependent T cell activation". J. Exp. Med. 183 (6): 2541–50. doi:10.1084/jem.183.6.2541. PMC 2192609. PMID 8676075.
- ↑ Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, Thompson CB, Bluestone JA (August 1994). "CTLA-4 can function as a negative regulator of T cell activation". Immunity. 1 (5): 405–13. doi:10.1016/1074-7613(94)90071-x. PMID 7882171.
- ↑ Harding FA, McArthur JG, Gross JA, Raulet DH, Allison JP (1992). "CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones". Nature. 356 (6370): 607–9. doi:10.1038/356607a0. PMID 1313950.
- ↑ Magistrelli G, Jeannin P, Herbault N, Benoit De Coignac A, Gauchat JF, Bonnefoy JY, Delneste Y (November 1999). "A soluble form of CTLA-4 generated by alternative splicing is expressed by nonstimulated human T cells". Eur. J. Immunol. 29 (11): 3596–602. doi:10.1002/(SICI)1521-4141(199911)29:11<3596::AID-IMMU3596>3.0.CO;2-Y. PMID 10556814.
- ↑ Lee KM, Chuang E, Griffin M, Khattri R, Hong DK, Zhang W, Straus D, Samelson LE, Thompson CB, Bluestone JA (1998). "Molecular basis of T cell inactivation by CTLA-4". Science. 282 (5397): 2263–6. doi:10.1126/science.282.5397.2263. PMID 9856951.
- ↑ Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, Schmidt EM, Baker J, Jeffery LE, Kaur S, Briggs Z, Hou TZ, Futter CE, Anderson G, Walker LS, Sansom DM (2011). "Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4". Science. 332 (6029): 600–3. doi:10.1126/science.1202947. PMC 3198051. PMID 21474713.
- ↑ Chen J, Ganguly A, Mucsi AD, Meng J, Yan J, Detampel P, Munro F, Zhang Z, Wu M, Hari A, Stenner MD, Zheng W, Kubes P, Xia T, Amrein MW, Qi H, Shi Y (February 2017). "Strong adhesion by regulatory T cells induces dendritic cell cytoskeletal polarization and contact-dependent lethargy". The Journal of Experimental Medicine. 214 (2): 327–338. doi:10.1084/jem.20160620. PMC 5294852. PMID 28082358.
- ↑ Knieke K, Lingel H, Chamaon K, Brunner-Weinzierl MC (2012). "Migration of Th1 lymphocytes is regulated by CD152 (CTLA-4)-mediated signaling via PI3 kinase-dependent Akt activation". PLoS ONE. 7 (3): e31391. doi:10.1371/journal.pone.0031391. PMC 3295805. PMID 22412835.
- ↑ Schneider H, Downey J, Smith A, Zinselmeyer BH, Rush C, Brewer JM, Wei B, Hogg N, Garside P, Rudd CE (September 2006). "Reversal of the TCR stop signal by CTLA-4". Science. 313 (5795): 1972–5. doi:10.1126/science.1131078. PMID 16931720.
- ↑ Rudd CE, Taylor A, Schneider H (May 2009). "CD28 and CTLA-4 coreceptor expression and signal transduction". Immunol. Rev. 229 (1): 12–26. doi:10.1111/j.1600-065X.2009.00770.x. PMC 4186963. PMID 19426212.
- ↑ Fife BT, Pauken KE, Eagar TN, Obu T, Wu J, Tang Q, Azuma M, Krummel MF, Bluestone JA (November 2009). "Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal". Nat. Immunol. 10 (11): 1185–92. doi:10.1038/ni.1790. PMC 2778301. PMID 19783989.
- ↑ Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, Arce F, Roddie C, Henry JY, Yagita H, Wolchok JD, Peggs KS, Ravetch JV, Allison JP, Quezada SA (2013). "Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma". J. Exp. Med. 210 (9): 1695–710. doi:10.1084/jem.20130579. PMC 3754863. PMID 23897981.
- ↑ 20.0 20.1 20.2 Kuehn HS, Ouyang W, Lo B, Deenick EK, Niemela JE, Avery DT, Schickel JN, Tran DQ, Stoddard J, Zhang Y, Frucht DM, Dumitriu B, Scheinberg P, Folio LR, Frein CA, Price S, Koh C, Heller T, Seroogy CM, Huttenlocher A, Rao VK, Su HC, Kleiner D, Notarangelo LD, Rampertaap Y, Olivier KN, McElwee J, Hughes J, Pittaluga S, Oliveira JB, Meffre E, Fleisher TA, Holland SM, Lenardo MJ, Tangye SG, Uzel G (2014). "Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4". Science. 345 (6204): 1623–7. doi:10.1126/science.1255904. PMC 4371526. PMID 25213377.
- ↑ 21.0 21.1 21.2 Schubert D, Bode C, Kenefeck R, Hou TZ, Wing JB, Kennedy A, Bulashevska A, Petersen BS, Schäffer AA, Grüning BA, Unger S, Frede N, Baumann U, Witte T, Schmidt RE, Dueckers G, Niehues T, Seneviratne S, Kanariou M, Speckmann C, Ehl S, Rensing-Ehl A, Warnatz K, Rakhmanov M, Thimme R, Hasselblatt P, Emmerich F, Cathomen T, Backofen R, Fisch P, Seidl M, May A, Schmitt-Graeff A, Ikemizu S, Salzer U, Franke A, Sakaguchi S, Walker LS, Sansom DM, Grimbacher B (2014). "Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations". Nat. Med. 20 (12): 1410–6. doi:10.1038/nm.3746. PMC 4668597. PMID 25329329.
- ↑ Zeissig S, Petersen BS, Tomczak M, Melum E, Huc-Claustre E, Dougan SK, Laerdahl JK, Stade B, Forster M, Schreiber S, Weir D, Leichtner AM, Franke A, Blumberg RS (2014). "Early-onset Crohn's disease and autoimmunity associated with a variant in CTLA-4". Gut. 64: 1–9. doi:10.1136/gutjnl-2014-308541. PMC 4512923. PMID 25367873.
- ↑ 23.0 23.1 23.2 Lee S, Moon JS, Lee CR, Kim HE, Baek SM, Hwang S, Kang GH, Seo JK, Shin CH, Kang HJ, Ko SJ, Park SG, Choi M (2016). "Abatacept alleviates severe autoimmune symptoms in a patient carrying a de novo variant in CTLA-4". J Allergy Clin Immunol. 137: 327–30. doi:10.1016/j.jaci.2015.08.036. PMID 26478010.
- ↑ Westhovens, R., et al, Abatacept (CTLA4Ig) treatment increases the remission rate in rheumatoid arthritis patients refractory to methotrexate treatment, Meeting Abstract, Arthritis Research & Therapy 6(Suppl 1):86, 24 February 2004. doi:10.1186/ar1128. Accessed 2015-11-14.
- ↑ Pardoll DM (April 2012). "The blockade of immune checkpoints in cancer immunotherapy". Nat. Rev. Cancer. 12 (4): 252–64. doi:10.1038/nrc3239. PMC 4856023. PMID 22437870.
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- ↑ Chuang E, Alegre ML, Duckett CS, Noel PJ, Vander Heiden MG, Thompson CB (July 1997). "Interaction of CTLA-4 with the clathrin-associated protein AP50 results in ligand-independent endocytosis that limits cell surface expression". J. Immunol. 159 (1): 144–51. PMID 9200449.
- ↑ Peach RJ, Bajorath J, Naemura J, Leytze G, Greene J, Aruffo A, Linsley PS (September 1995). "Both extracellular immunoglobin-like domains of CD80 contain residues critical for binding T cell surface receptors CTLA-4 and CD28". J. Biol. Chem. 270 (36): 21181–7. doi:10.1074/jbc.270.36.21181. PMID 7545666.
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- Human CTLA4 genome location and CTLA4 gene details page in the UCSC Genome Browser.
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