Cytotoxic T-lymphocyte associated protein 4

{{Short description|Mammalian protein found in humans}} {{Technical|date=September 2017}} {{Infobox gene}} '''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 is constitutively expressed in regulatory T cells but only upregulated in conventional T cells after activation – a phenomenon which is particularly notable in cancers.<ref name=":0">{{cite journal | vauthors = Syn NL, Teng MW, Mok TS, Soo RA | title = De-novo and acquired resistance to immune checkpoint targeting | journal = The Lancet. Oncology | volume = 18 | issue = 12 | pages = e731–e741 | date = December 2017 | pmid = 29208439 | doi = 10.1016/s1470-2045(17)30607-1 }}</ref> It acts as an "off" switch when bound to CD80 or CD86 on the surface of antigen-presenting cells. It is encoded by the ''CTLA4'' gene in humans, and by the ''Ctla4'' gene in mice.<!-- current gene symbol, see infobox; the refs are oudated --><ref name="pmid3496540">{{cite journal | vauthors = Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, Golstein P | title = A new member of the immunoglobulin superfamily--CTLA-4 | journal = Nature | volume = 328 | issue = 6127 | pages = 267–70 | year = 1987 | pmid = 3496540 | doi = 10.1038/328267a0 | bibcode = 1987Natur.328..267B | s2cid = 4316396 }}| Available online 9 Feb 2026 on at https://www.nature.com/articles/328267a0.</ref><ref name="pmid3220103">{{cite journal | vauthors = Dariavach P, Mattéi MG, Golstein P, Lefranc MP | title = Human Ig superfamily CTLA-4 gene: chromosomal localization and identity of protein sequence between murine and human CTLA-4 cytoplasmic domains | journal = European Journal of Immunology | volume = 18 | issue = 12 | pages = 1901–5 | date = December 1988 | pmid = 3220103 | doi = 10.1002/eji.1830181206 | s2cid = 34071559 }}</ref>

== History == CTLA-4 was first identified in 1991 as a second receptor for the T cell costimulation ligand B7.<ref>{{cite journal | author = Bashyam, Hema | title = CTLA-4: From conflict to clinic | journal = J Exp Med | volume = 204 | number = 6 | page = 1243 | date = June 2007 | pmid = 17632849 | pmc=2118622| doi = 10.1084/jem.2046fta}}</ref> 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.<ref name = "Waterhouse_1995">{{cite journal | vauthors = Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW | display-authors = 6 | title = Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4 | journal = Science | volume = 270 | issue = 5238 | pages = 985–8 | date = November 1995 | pmid = 7481803 | doi = 10.1126/science.270.5238.985 | jstor = 2888113 | bibcode = 1995Sci...270..985W | s2cid = 45993765 }}</ref><ref>{{cite journal | vauthors = Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH | title = Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4 | journal = Immunity | volume = 3 | issue = 5 | pages = 541–7 | date = November 1995 | pmid = 7584144 | doi = 10.1016/1074-7613(95)90125-6 | url = http://www.cell.com/immunity/pdf/1074-7613(95)90125-6.pdf | doi-access = free }}</ref> Previous studies from several labs had used methods which could not definitively define the function of CTLA-4, and were contradictory.<ref>{{cite journal | vauthors = Pardoll DM | title = Immunology beats cancer: a blueprint for successful translation | journal = Nature Immunology | volume = 13 | issue = 12 | pages = 1129–32 | date = December 2012 | pmid = 23160205 | pmc = 4659410 | doi = 10.1038/ni.2392 }}</ref>

== Function == CTLA-4 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,<ref name="pmid7543139">{{cite journal | vauthors = Krummel MF, Allison JP | title = CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation | journal = The Journal of Experimental Medicine | volume = 182 | issue = 2 | pages = 459–65 | date = August 1995 | pmid = 7543139 | pmc = 2192127 | doi = 10.1084/jem.182.2.459 }}</ref><ref name="pmid8676075">{{cite journal | vauthors = Walunas TL, Bakker CY, Bluestone JA | title = CTLA-4 ligation blocks CD28-dependent T cell activation | journal = The Journal of Experimental Medicine | volume = 183 | issue = 6 | pages = 2541–50 | date = June 1996 | pmid = 8676075 | pmc = 2192609 | doi = 10.1084/jem.183.6.2541 }}</ref><ref name="pmid7882171">{{cite journal | vauthors = Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, Thompson CB, Bluestone JA | display-authors = 6 | title = CTLA-4 can function as a negative regulator of T cell activation | journal = Immunity | volume = 1 | issue = 5 | pages = 405–13 | date = August 1994 | pmid = 7882171 | doi = 10.1016/1074-7613(94)90071-x }}</ref><ref name = "Waterhouse_1995" /> whereas CD28 transmits a stimulatory signal.<ref name="pmid1313950">{{cite journal | vauthors = Harding FA, McArthur JG, Gross JA, Raulet DH, Allison JP | title = CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones | journal = Nature | volume = 356 | issue = 6370 | pages = 607–9 | date = April 1992 | pmid = 1313950 | doi = 10.1038/356607a0 | bibcode = 1992Natur.356..607H | s2cid = 4333730 }}</ref><ref name="pmid10556814">{{cite journal | vauthors = Magistrelli G, Jeannin P, Herbault N, Benoit De Coignac A, Gauchat JF, Bonnefoy JY, Delneste Y | title = A soluble form of CTLA-4 generated by alternative splicing is expressed by nonstimulated human T cells | journal = European Journal of Immunology | volume = 29 | issue = 11 | pages = 3596–602 | date = November 1999 | pmid = 10556814 | doi = 10.1002/(SICI)1521-4141(199911)29:11<3596::AID-IMMU3596>3.0.CO;2-Y | doi-access = free }}</ref> 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 the signal.<ref name="pmid9856951">{{cite journal | vauthors = Lee KM, Chuang E, Griffin M, Khattri R, Hong DK, Zhang W, Straus D, Samelson LE, Thompson CB, Bluestone JA | display-authors = 6 | title = Molecular basis of T cell inactivation by CTLA-4 | journal = Science | volume = 282 | issue = 5397 | pages = 2263–6 | date = December 1998 | pmid = 9856951 | doi = 10.1126/science.282.5397.2263 | bibcode = 1998Sci...282.2263L | doi-access = free }}</ref> 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.<ref name="pmid21474713">{{cite journal | vauthors = 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 | display-authors = 6 | title = Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4 | journal = Science | volume = 332 | issue = 6029 | pages = 600–3 | date = April 2011 | pmid = 21474713 | pmc = 3198051 | doi = 10.1126/science.1202947 | bibcode = 2011Sci...332..600Q }}</ref>

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.<ref>{{cite journal | vauthors = 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 | display-authors = 6 | title = Strong adhesion by regulatory T cells induces dendritic cell cytoskeletal polarization and contact-dependent lethargy | journal = The Journal of Experimental Medicine | volume = 214 | issue = 2 | pages = 327–338 | date = February 2017 | pmid = 28082358 | pmc = 5294852 | doi = 10.1084/jem.20160620 }}</ref>

CTLA-4 may also function via modulation of cell motility and/or signaling through PI3 kinase.<ref name="pmid22412835">{{cite journal | vauthors = Knieke K, Lingel H, Chamaon K, Brunner-Weinzierl MC | title = Migration of Th1 lymphocytes is regulated by CD152 (CTLA-4)-mediated signaling via PI3 kinase-dependent Akt activation | journal = PLOS ONE | volume = 7 | issue = 3 | article-number = e31391 | year = 2012 | pmid = 22412835 | pmc = 3295805 | doi = 10.1371/journal.pone.0031391 | bibcode = 2012PLoSO...731391K | doi-access = free }}</ref> Early multiphoton microscopy studies observing T-cell motility in intact lymph nodes appeared to give evidence for the so-called 'reverse-stop signaling model'.<ref name="pmid16931720">{{cite journal | vauthors = Schneider H, Downey J, Smith A, Zinselmeyer BH, Rush C, Brewer JM, Wei B, Hogg N, Garside P, Rudd CE | s2cid = 27123046 | display-authors = 6 | title = Reversal of the TCR stop signal by CTLA-4 | journal = Science | volume = 313 | issue = 5795 | pages = 1972–5 | date = September 2006 | pmid = 16931720 | doi = 10.1126/science.1131078 | bibcode = 2006Sci...313.1972S }}</ref> In this model CTLA-4 reverses the TCR-induced 'stop signal' needed for firm contact between T cells and antigen-presenting cells (APCs).<ref name="pmid19426212">{{cite journal | vauthors = Rudd CE, Taylor A, Schneider H | title = CD28 and CTLA-4 coreceptor expression and signal transduction | journal = Immunological Reviews | volume = 229 | issue = 1 | pages = 12–26 | date = May 2009 | pmid = 19426212 | pmc = 4186963 | doi = 10.1111/j.1600-065X.2009.00770.x }}</ref> 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.<ref name="pmid19783989">{{cite journal | vauthors = Fife BT, Pauken KE, Eagar TN, Obu T, Wu J, Tang Q, Azuma M, Krummel MF, Bluestone JA | display-authors = 6 | title = Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal | journal = Nature Immunology | volume = 10 | issue = 11 | pages = 1185–92 | date = November 2009 | pmid = 19783989 | pmc = 2778301 | doi = 10.1038/ni.1790 }}</ref> Antibodies to CTLA-4 may exert additional effects when used in vivo, by binding and thereby depleting regulatory T cells.<ref name="pmid23897981">{{cite journal | vauthors = 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 | display-authors = 6 | title = Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma | journal = The Journal of Experimental Medicine | volume = 210 | issue = 9 | pages = 1695–710 | date = August 2013 | pmid = 23897981 | pmc = 3754863 | doi = 10.1084/jem.20130579 }}</ref>

== Structure == 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.

==Clinical significance== 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,<ref>{{cite journal | vauthors = Westra HJ, Martínez-Bonet M, Onengut-Gumuscu S, Lee A, Luo Y, Teslovich N, Worthington J, Martin J, Huizinga T, Klareskog L, Rantapaa-Dahlqvist S, Chen WM, Quinlan A, Todd JA, Eyre S, Nigrovic PA, Gregersen PK, Rich SS, Raychaudhuri S | display-authors = 6 | title = Fine-mapping and functional studies highlight potential causal variants for rheumatoid arthritis and type 1 diabetes | journal = Nature Genetics | volume = 50 | issue = 10 | pages = 1366–1374 | date = October 2018 | pmid = 30224649 | pmc = 6364548 | doi = 10.1038/s41588-018-0216-7 }}</ref> 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=== 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 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.<ref name="Kuehn Science 2014">{{cite journal | vauthors = 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 | display-authors = 6 | title = Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4 | journal = Science | volume = 345 | issue = 6204 | pages = 1623–1627 | date = September 2014 | pmid = 25213377 | pmc = 4371526 | doi = 10.1126/science.1255904 | bibcode = 2014Sci...345.1623K }}</ref> 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.<ref name="Grimbacher Nature medicine 2014">{{cite journal | vauthors = 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 | display-authors = 6 | title = Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations | journal = Nature Medicine | volume = 20 | issue = 12 | pages = 1410–1416 | date = December 2014 | pmid = 25329329 | pmc = 4668597 | doi = 10.1038/nm.3746 }}</ref>

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.

====Clinical and laboratory manifestations==== Symptomatic patients with CTLA-4 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<ref name="pmid34097529">{{cite journal | vauthors = Kaninia S, Grammatikos A, Urankar K, Renowden SA, Patel NK, Gompels MM, Rice CM | title = CNS demyelination associated with immune dysregulation and a novel ''CTLA-4'' variant | journal = Multiple Sclerosis | volume = 27 | issue = 9 | pages = 1464–1467 | date = August 2021 | pmid = 34097529 | pmc = 8358566 | doi = 10.1177/1352458520963896 }}</ref><ref name="pmid33956248">{{cite journal | vauthors = Grammatikos A, Johnston S, Rice CM, Gompels M | title = A Family with a Novel CTLA4 Haploinsufficiency Mutation and Neurological Symptoms | journal = Journal of Clinical Immunology | volume = 41 | issue = 6 | pages = 1411–1416 | date = August 2021 | pmid = 33956248 | pmc = 8310858 | doi = 10.1007/s10875-021-01027-1 }}</ref> 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.<ref name="Kuehn Science 2014" /><ref name="Grimbacher Nature medicine 2014" /><ref name=Zeissig>{{cite journal | vauthors = 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 | display-authors = 6 | title = Early-onset Crohn's disease and autoimmunity associated with a variant in CTLA-4 | journal = Gut | volume = 64 | issue = 12 | pages = 1889–97 | date = December 2015 | pmid = 25367873 | pmc = 4512923 | doi = 10.1136/gutjnl-2014-308541 }}</ref><ref name=MChoi>{{cite journal | vauthors = Lee S, Moon JS, Lee CR, Kim HE, Baek SM, Hwang S, Kang GH, Seo JK, Shin CH, Kang HJ, Ko JS, Park SG, Choi M | display-authors = 6 | title = Abatacept alleviates severe autoimmune symptoms in a patient carrying a de novo variant in CTLA-4 | journal = The Journal of Allergy and Clinical Immunology | volume = 137 | issue = 1 | pages = 327–330 | date = January 2016 | pmid = 26478010 | doi = 10.1016/j.jaci.2015.08.036 | doi-access = free }}</ref> 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 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.<ref name="Kuehn Science 2014" /><ref name="Grimbacher Nature medicine 2014" /><ref name="MChoi" />

====Treatment==== 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 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 the patient's severe anemia and diarrhea (3L/day) and brought 3-year-long hospitalization to an end.<ref name="MChoi" />

===Agonists to reduce immune activity=== 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.<ref>{{cite journal | vauthors = Westhovens R | display-authors = etal | year = 2004 | title = Abatacept (CTLA4Ig) treatment increases the remission rate in rheumatoid arthritis patients refractory to methotrexate treatment | journal = Arthritis Research & Therapy | volume = 6 | issue = Suppl 1 | page = 86 | pmc=2833769| doi = 10.1186/ar1128 | doi-access = free }}</ref> 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 CTLA-4 (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).<ref name=":0" /> This therapy was the first approved immune checkpoint blockade therapy.<ref name="Pardoll_2012">{{cite journal | vauthors = Pardoll DM | title = The blockade of immune checkpoints in cancer immunotherapy | journal = Nature Reviews. Cancer | volume = 12 | issue = 4 | pages = 252–64 | date = March 2012 | pmid = 22437870 | pmc = 4856023 | doi = 10.1038/nrc3239 }}</ref> Another is tremelimumab.<ref name=":0" />

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".<ref>{{cite news |title=The Nobel Prize in Physiology or Medicine 2018 |url=https://www.nobelprize.org/prizes/medicine/2018/summary/ |access-date=3 July 2023 |work=NobelPrize.org}}</ref>

== Interactions == CTLA-4 has been shown to interact with: * AP2M1,<ref name="pmid11583591">{{cite journal | vauthors = Follows ER, McPheat JC, Minshull C, Moore NC, Pauptit RA, Rowsell S, Stacey CL, Stanway JJ, Taylor IW, Abbott WM | display-authors = 6 | title = Study of the interaction of the medium chain mu 2 subunit of the clathrin-associated adapter protein complex 2 with cytotoxic T-lymphocyte antigen 4 and CD28 | journal = The Biochemical Journal | volume = 359 | issue = Pt 2 | pages = 427–34 | date = October 2001 | pmid = 11583591 | pmc = 1222163 | doi = 10.1042/0264-6021:3590427 }}</ref><ref name="pmid9200449">{{cite journal | vauthors = Chuang E, Alegre ML, Duckett CS, Noel PJ, Vander Heiden MG, Thompson CB | title = Interaction of CTLA-4 with the clathrin-associated protein AP50 results in ligand-independent endocytosis that limits cell surface expression | journal = Journal of Immunology | volume = 159 | issue = 1 | pages = 144–51 | date = July 1997 | doi = 10.4049/jimmunol.159.1.144 | pmid = 9200449 | s2cid = 25449038 | doi-access = free }}</ref> * CD80,<ref name="pmid7545666">{{cite journal | vauthors = Peach RJ, Bajorath J, Naemura J, Leytze G, Greene J, Aruffo A, Linsley PS | title = Both extracellular immunoglobin-like domains of CD80 contain residues critical for binding T cell surface receptors CTLA-4 and CD28 | journal = The Journal of Biological Chemistry | volume = 270 | issue = 36 | pages = 21181–7 | date = September 1995 | pmid = 7545666 | doi = 10.1074/jbc.270.36.21181 | doi-access = free }}</ref><ref name="pmid11279502">{{cite journal | vauthors = Stamper CC, Zhang Y, Tobin JF, Erbe DV, Ikemizu S, Davis SJ, Stahl ML, Seehra J, Somers WS, Mosyak L | display-authors = 6 | title = Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses | journal = Nature | volume = 410 | issue = 6828 | pages = 608–11 | date = March 2001 | pmid = 11279502 | doi = 10.1038/35069118 | bibcode = 2001Natur.410..608S | s2cid = 4329622 }}</ref> * CD86, * SHP-2, and * PPP2R5A.<ref name="pmid11994459">{{cite journal | vauthors = Baroja ML, Vijayakrishnan L, Bettelli E, Darlington PJ, Chau TA, Ling V, Collins M, Carreno BM, Madrenas J, Kuchroo VK | display-authors = 6 | title = Inhibition of CTLA-4 function by the regulatory subunit of serine/threonine phosphatase 2A | journal = Journal of Immunology | volume = 168 | issue = 10 | pages = 5070–8 | date = May 2002 | pmid = 11994459 | doi = 10.4049/jimmunol.168.10.5070 | doi-access = free }}</ref>

== References == {{reflist|35em}}

== Further reading == {{refbegin|35em}} * {{cite journal | vauthors = Liossis SN, Sfikakis PP, Tsokos GC | title = Immune cell signaling aberrations in human lupus | journal = Immunologic Research | volume = 18 | issue = 1 | pages = 27–39 | date = August 1998 | pmid = 9724847 | doi = 10.1007/BF02786511 | s2cid = 13581332 | url = https://zenodo.org/record/1232566 }} * {{cite book | vauthors = Chang TT, Kuchroo VK, Sharpe AH | title = Signal Transduction Pathways in Autoimmunity | chapter = Role of the B7-CD28/CTLA-4 pathway in autoimmune disease | volume = 5 | pages = 113–30 | year = 2002 | pmid = 11826754 | doi = 10.1159/000060550 | isbn = 978-3-8055-7308-5 | series = Current Directions in Autoimmunity }} * {{cite journal | vauthors = Alizadeh M, Babron MC, Birebent B, Matsuda F, Quelvennec E, Liblau R, Cournu-Rebeix I, Momigliano-Richiardi P, Sequeiros J, Yaouanq J, Genin E, Vasilescu A, Bougerie H, Trojano M, Martins Silva B, Maciel P, Clerget-Darpoux F, Clanet M, Edan G, Fontaine B, Semana G | display-authors = 6 | title = Genetic interaction of CTLA-4 with HLA-DR15 in multiple sclerosis patients | journal = Annals of Neurology | volume = 54 | issue = 1 | pages = 119–22 | date = July 2003 | pmid = 12838528 | doi = 10.1002/ana.10617 | s2cid = 9216025 }} * {{cite journal | vauthors = Chistiakov DA, Turakulov RI | title = CTLA-4 and its role in autoimmune thyroid disease | journal = Journal of Molecular Endocrinology | volume = 31 | issue = 1 | pages = 21–36 | date = August 2003 | pmid = 12914522 | doi = 10.1677/jme.0.0310021 | doi-access = free }} * {{cite journal | vauthors = Vaidya B, Pearce S | title = The emerging role of the CTLA-4 gene in autoimmune endocrinopathies | journal = European Journal of Endocrinology | volume = 150 | issue = 5 | pages = 619–26 | date = May 2004 | pmid = 15132716 | doi = 10.1530/eje.0.1500619 | doi-access = free }} * {{cite journal | vauthors = Brand O, Gough S, Heward J | title = HLA, CTLA-4 and PTPN22: the shared genetic master-key to autoimmunity? | journal = Expert Reviews in Molecular Medicine | volume = 7 | issue = 23 | pages = 1–15 | date = October 2005 | pmid = 16229750 | doi = 10.1017/S1462399405009981 | s2cid = 841442 }} * {{cite journal | vauthors = Kavvoura FK, Akamizu T, Awata T, Ban Y, Chistiakov DA, Frydecka I, Ghaderi A, Gough SC, Hiromatsu Y, Ploski R, Wang PW, Ban Y, Bednarczuk T, Chistiakova EI, Chojm M, Heward JM, Hiratani H, Juo SH, Karabon L, Katayama S, Kurihara S, Liu RT, Miyake I, Omrani GH, Pawlak E, Taniyama M, Tozaki T, Ioannidis JP | display-authors = 6 | title = Cytotoxic T-lymphocyte associated antigen 4 gene polymorphisms and autoimmune thyroid disease: a meta-analysis | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 92 | issue = 8 | pages = 3162–70 | date = August 2007 | pmid = 17504905 | doi = 10.1210/jc.2007-0147 | doi-access = free }} {{refend}}

== External links == * {{UCSC gene info|CTLA4}} * {{PDBe-KB2|P16410|Cytotoxic T-lymphocyte protein 4}}

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Category:Clusters of differentiation Category:T cells