Genomes and Genes
Gene Symbol: Ctla4
Description: cytotoxic T-lymphocyte-associated protein 4
Alias: Cd152, Ctla-4, Ly-56, cytotoxic T-lymphocyte protein 4, CD152 antigen, cytotoxic T-lymphocyte-associated antigen 4
- Ostrov D, Shi W, Schwartz J, Almo S, Nathenson S. Structure of murine CTLA-4 and its role in modulating T cell responsiveness. Science. 2000;290:816-9 pubmed..This organization allows each CTLA-4 dimer to bind two bivalent B7 molecules and suggests that a periodic arrangement of these components within the immunological synapse may contribute to the regulation of T cell responsiveness. ..
- Chambers C, Kuhns M, Allison J. Cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates primary and secondary peptide-specific CD4(+) T cell responses. Proc Natl Acad Sci U S A. 1999;96:8603-8 pubmed..These results demonstrate that CTLA-4 is a key regulator of peptide-specific CD4(+) T cell responses and support the model that CTLA-4 plays a differential role in maintaining T cell homeostasis of CD4(+) vs. CD8(+) T cells. ..
- Waterhouse P, Penninger J, Timms E, Wakeham A, Shahinian A, Lee K, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995;270:985-8 pubmed..Thus, CTLA-4 acts as a negative regulator of T cell activation and is vital for the control of lymphocyte homeostasis. ..
- Chambers C, Cado D, Truong T, Allison J. Thymocyte development is normal in CTLA-4-deficient mice. Proc Natl Acad Sci U S A. 1997;94:9296-301 pubmed..Thus it appears that CTLA-4 is primarily involved in the regulation of peripheral T cell activation. ..
- Schmidt E, Wang C, Ryan G, Clough L, Qureshi O, Goodall M, et al. Ctla-4 controls regulatory T cell peripheral homeostasis and is required for suppression of pancreatic islet autoimmunity. J Immunol. 2009;182:274-82 pubmed..Collectively, these data suggest that the proliferation of Treg in the periphery is tuned by CTLA-4 signals and that Treg expression of CTLA-4 is required for regulation of pancreas autoimmunity. ..
- Kolar P, Knieke K, Hegel J, Quandt D, Burmester G, Hoff H, et al. CTLA-4 (CD152) controls homeostasis and suppressive capacity of regulatory T cells in mice. Arthritis Rheum. 2009;60:123-32 pubmed publisher..Expression of CTLA-4 on Treg cells serves to control T cell proliferation, to confer resistance against AICD, and to maintain the suppressive function of Treg cells. ..
- Maszyna F, Hoff H, Kunkel D, Radbruch A, Brunner Weinzierl M. Diversity of clonal T cell proliferation is mediated by differential expression of CD152 (CTLA-4) on the cell surface of activated individual T lymphocytes. J Immunol. 2003;171:3459-66 pubmedInhibitory effects of CD152 (CTLA-4) engagement during T cell activation have been described...
- Walker L, Ausubel L, Chodos A, Bekarian N, Abbas A. CTLA-4 differentially regulates T cell responses to endogenous tissue protein versus exogenous immunogen. J Immunol. 2002;169:6202-9 pubmed..Thus, CTLA-4 may preferentially dampen pathologic immune responses to self proteins while permitting protective immunity to foreign agents. ..
- Schneider H, Downey J, Smith A, Zinselmeyer B, Rush C, Brewer J, et al. Reversal of the TCR stop signal by CTLA-4. Science. 2006;313:1972-5 pubmed..These results suggest a fundamentally different model of reverse stop signaling, by which CTLA-4 modulates the threshold for T cell activation and protects against autoimmunity. ..
- Bachmann M, Waterhouse P, Speiser D, McKall Faienza K, Mak T, Ohashi P. Normal responsiveness of CTLA-4-deficient anti-viral cytotoxic T cells. J Immunol. 1998;160:95-100 pubmed
- Gozalo Sanmillan S, McNally J, Lin M, Chambers C, Berg L. Cutting edge: two distinct mechanisms lead to impaired T cell homeostasis in Janus kinase 3- and CTLA-4-deficient mice. J Immunol. 2001;166:727-30 pubmed..These findings provide insight into the diverse mechanisms controlling T cell homeostasis. ..
- Khattri R, Auger J, Griffin M, Sharpe A, Bluestone J. Lymphoproliferative disorder in CTLA-4 knockout mice is characterized by CD28-regulated activation of Th2 responses. J Immunol. 1999;162:5784-91 pubmed..Thus, CTLA-4 regulates CD28-dependent peripheral activation of CD4+ T cells. This process results in apoptosis-resistant, CD4+ T cells with a predominantly Th2 phenotype that may be involved in the lethal phenotype in these animals. ..
- Mandelbrot D, Oosterwegel M, Shimizu K, Yamada A, Freeman G, Mitchell R, et al. B7-dependent T-cell costimulation in mice lacking CD28 and CTLA4. J Clin Invest. 2001;107:881-7 pubmedTo examine whether B7 costimulation can be mediated by a molecule on T cells that is neither CD28 nor CTLA4, we generated mice lacking both of these receptors...
- Wicker L, Chamberlain G, Hunter K, Rainbow D, Howlett S, Tiffen P, et al. Fine mapping, gene content, comparative sequencing, and expression analyses support Ctla4 and Nramp1 as candidates for Idd5.1 and Idd5.2 in the nonobese diabetic mouse. J Immunol. 2004;173:164-73 pubmed..B10 congenic strains, Idd5.1 has been defined to a 2.1-Mb region containing only four genes, Ctla4, Icos, Als2cr19, and Nrp2 (neuropilin-2), thereby excluding a major candidate gene, Cd28...
- Tivol E, Gorski J. Re-establishing peripheral tolerance in the absence of CTLA-4: complementation by wild-type T cells points to an indirect role for CTLA-4. J Immunol. 2002;169:1852-8 pubmed..In addition, a rapid reduction in the ratio of CTLA-4-deficient to wild-type cells was observed. We propose two possible indirect mechanisms by which CTLA-4 may function in the establishment and maintenance of peripheral tolerance. ..
- Anderson K, Czinn S, Redline R, Blanchard T. Induction of CTLA-4-mediated anergy contributes to persistent colonization in the murine model of gastric Helicobacter pylori infection. J Immunol. 2006;176:5306-13 pubmed..These results suggest that CTLA-4 engagement induces and maintains functional inactivation of H. pylori-specific T cells during H. pylori infection resulting in a reduced immune response. ..
- Friedline R, Brown D, Nguyen H, Kornfeld H, Lee J, Zhang Y, et al. CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance. J Exp Med. 2009;206:421-34 pubmed publisher..blastocyst and BM chimaeras as well as in vivo T cell transfer systems, we demonstrate that in vivo regulation of Ctla4(-/-) T cells in trans by CTLA-4-sufficient T cells is a reversible process that requires the persistent presence ..
- Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med. 2000;192:303-10 pubmed..This unique function of CTLA-4 could be exploited to potentiate T cell-mediated immunoregulation, and thereby to induce immunologic tolerance or to control autoimmunity. ..
- Zheng S, Wang J, Stohl W, Kim K, Gray J, Horwitz D. TGF-beta requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4+CD25+ regulatory cells. J Immunol. 2006;176:3321-9 pubmed..Although natural CD4+CD25+ cells develop normally in CTLA-4(-/-) mice, the lack of TGF-beta-induced, peripheral CD4+CD25+ suppressor cells in these mice may contribute to their rapid demise. ..
- Tang Q, Boden E, Henriksen K, Bour Jordan H, Bi M, Bluestone J. Distinct roles of CTLA-4 and TGF-beta in CD4+CD25+ regulatory T cell function. Eur J Immunol. 2004;34:2996-3005 pubmed..These results help explain contradictions in the literature and support the existence of functionally distinct Treg. ..
- Wing K, Onishi Y, Prieto Martin P, Yamaguchi T, Miyara M, Fehervari Z, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322:271-5 pubmed publisher..Thus, natural Tregs may critically require CTLA-4 to suppress immune responses by affecting the potency of antigen-presenting cells to activate other T cells. ..
- Yokosuka T, Kobayashi W, Takamatsu M, Sakata Sogawa K, Zeng H, Hashimoto Tane A, et al. Spatiotemporal basis of CTLA-4 costimulatory molecule-mediated negative regulation of T cell activation. Immunity. 2010;33:326-39 pubmed publisher..The CTLA-4-mediated suppression was demonstrated by the in vitro anergy induction in regulatory T cells constitutively expressing CTLA-4. These results show the dynamic mechanism of CTLA-4-mediated T cell suppression at the cSMAC. ..
- Verhagen J, Genolet R, Britton G, Stevenson B, Sabatos Peyton C, Dyson J, et al. CTLA-4 controls the thymic development of both conventional and regulatory T cells through modulation of the TCR repertoire. Proc Natl Acad Sci U S A. 2013;110:E221-30 pubmed publisherCytotoxic T lymphocyte-associated antigen-4 (CTLA-4; CD152) is of pivotal importance for self-tolerance, with deficiency or unfavorable polymorphisms leading to autoimmune disease...
- Eagar T, Karandikar N, Bluestone J, Miller S. The role of CTLA-4 in induction and maintenance of peripheral T cell tolerance. Eur J Immunol. 2002;32:972-81 pubmed
- Greenwald R, Boussiotis V, Lorsbach R, Abbas A, Sharpe A. CTLA-4 regulates induction of anergy in vivo. Immunity. 2001;14:145-55 pubmed..Thus, CTLA-4 has an essential role in determining the outcome of T cell encounter with a tolerogenic stimulus. ..
- Mandelbrot D, McAdam A, Sharpe A. B7-1 or B7-2 is required to produce the lymphoproliferative phenotype in mice lacking cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). J Exp Med. 1999;189:435-40 pubmed..This suggests that the inhibitory function of CTLA-4 can overcome strong CD28-mediated signaling in vivo. ..
- Chikuma S, Bluestone J. Expression of CTLA-4 and FOXP3 in cis protects from lethal lymphoproliferative disease. Eur J Immunol. 2007;37:1285-9 pubmed..These results suggest common attributes of both diseases, but expression of both CTLA-4 and FoxP3 on the same cell subset is essential to fully prevent LP disease. ..
- Pandiyan P, Gärtner D, Soezeri O, Radbruch A, Schulze Osthoff K, Brunner Weinzierl M. CD152 (CTLA-4) determines the unequal resistance of Th1 and Th2 cells against activation-induced cell death by a mechanism requiring PI3 kinase function. J Exp Med. 2004;199:831-42 pubmed..Here, we show that the genetic and antibody-mediated inactivation of CD152 (cytotoxic T lymphocyte antigen 4) in T helper (Th) effector cells reduced the frequency of nonapoptotic cells in ..
- Liu H, Hu B, Xu D, Liew F. CD4+CD25+ regulatory T cells cure murine colitis: the role of IL-10, TGF-beta, and CTLA4. J Immunol. 2003;171:5012-7 pubmed..effect of the regulatory T cells was completely blocked by treatment of the recipients with anti-IL-10R, anti-CTLA4, or anti-TGF-beta Ab...
- Knieke K, Hoff H, Maszyna F, Kolar P, Schrage A, Hamann A, et al. CD152 (CTLA-4) determines CD4 T cell migration in vitro and in vivo. PLoS ONE. 2009;4:e5702 pubmed publisher..The surface molecule CD152 (CTLA-4) is mostly considered as a negative regulator of T cell activation during immune responses...
- Alegre M, Shiels H, Thompson C, Gajewski T. Expression and function of CTLA-4 in Th1 and Th2 cells. J Immunol. 1998;161:3347-56 pubmed..We conclude that CTLA-4 can function to suppress the production of cytokines produced by both Th1 and Th2 cells. ..
- Oaks M, Hallett K, Penwell R, Stauber E, Warren S, Tector A. A native soluble form of CTLA-4. Cell Immunol. 2000;201:144-53 pubmed..Recombinant sCTLA-4 is a B7-binding protein and has immunomodulatory effects as measured by inhibition of the mixed leukocyte response. Human serum contains immunoreactive material consistent with a native soluble form of CTLA-4. ..
- Verhagen J, GabrysovÃ¡ L, Minaee S, Sabatos C, Anderson G, Sharpe A, et al. Enhanced selection of FoxP3+ T-regulatory cells protects CTLA-4-deficient mice from CNS autoimmune disease. Proc Natl Acad Sci U S A. 2009;106:3306-11 pubmed publisherIt is generally acknowledged that cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4/CD152) plays a pivotal role in the regulation of T-cell activation and the establishment of self-tolerance in the periphery...
- Lute K, May K, Lu P, Zhang H, Kocak E, Mosinger B, et al. Human CTLA4 knock-in mice unravel the quantitative link between tumor immunity and autoimmunity induced by anti-CTLA-4 antibodies. Blood. 2005;106:3127-33 pubmed..In order to address these 2 issues, we have generated human CTLA4 gene knock-in mice and used them to compare a panel of anti-human CTLA-4 antibodies for their ability to induce ..
- Vijayakrishnan L, Slavik J, Illes Z, Greenwald R, Rainbow D, Greve B, et al. An autoimmune disease-associated CTLA-4 splice variant lacking the B7 binding domain signals negatively in T cells. Immunity. 2004;20:563-75 pubmed..These data suggest that increased expression and negative signaling delivered by the liCTLA-4 may regulate development of T cell-mediated autoimmune diseases. ..
- Khattri R, Cox T, Yasayko S, Ramsdell F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol. 2003;4:337-42 pubmed..The forced expression of Foxp3 also delays disease in CTLA-4-/- mice, indicating that the Scurfin and CTLA-4 pathways may intersect and providing further insight into the T(R) cell lineage. ..
- Chambers C, Sullivan T, Truong T, Allison J. Secondary but not primary T cell responses are enhanced in CTLA-4-deficient CD8+ T cells. Eur J Immunol. 1998;28:3137-43 pubmed..These results suggest that CTLA-4 regulates antigen-specific memory CD8+ T cell responses. ..
- Pentcheva Hoang T, Egen J, Wojnoonski K, Allison J. B7-1 and B7-2 selectively recruit CTLA-4 and CD28 to the immunological synapse. Immunity. 2004;21:401-13 pubmed
- Ueda H, Howson J, Esposito L, Heward J, Snook H, Chamberlain G, et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature. 2003;423:506-11 pubmed..Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)--which encodes a vital negative regulatory molecule of the immune system--as candidates for primary determinants ..
- Waterhouse P, Bachmann M, Penninger J, Ohashi P, Mak T. Normal thymic selection, normal viability and decreased lymphoproliferation in T cell receptor-transgenic CTLA-4-deficient mice. Eur J Immunol. 1997;27:1887-92 pubmed..These results demonstrate that specific antigen is required for the lymphoproliferation observed in CTLA-4(-/-) mice, and that CTLA-4 deficiency does not lead to a gross defect in negative selection. ..
- Schwartz J, Zhang X, Nathenson S, Almo S. Structural mechanisms of costimulation. Nat Immunol. 2002;3:427-34 pubmed..An examination of the signaling mechanisms within the costimulatory receptor-ligand family provides an excellent framework to consider the general principles that are relevant to cell surface receptor-mediated signaling events. ..
- Schneider H, Valk E, da Rocha Dias S, Wei B, Rudd C. CTLA-4 up-regulation of lymphocyte function-associated antigen 1 adhesion and clustering as an alternate basis for coreceptor function. Proc Natl Acad Sci U S A. 2005;102:12861-6 pubmed..Our findings identify a potent role for CTLA-4 in directing integrin adhesion and provide an alternate mechanism to account for aspects of CTLA-4 function in T cell immunity. ..
- Greenwald R, Oosterwegel M, Van der Woude D, Kubal A, Mandelbrot D, Boussiotis V, et al. CTLA-4 regulates cell cycle progression during a primary immune response. Eur J Immunol. 2002;32:366-73 pubmed..Re-expression of the cell cycle inhibitor p27(kip1) is delayed in the absence of CTLA-4. These studies demonstrate that the B7 : CTLA-4 pathway exerts its major effects on T cell immune responses via regulation of the cell cycle. ..
- Tivol E, Boyd S, McKeon S, Borriello F, Nickerson P, Strom T, et al. CTLA4Ig prevents lymphoproliferation and fatal multiorgan tissue destruction in CTLA-4-deficient mice. J Immunol. 1997;158:5091-4 pubmed..The lack of long term protective effects of CTLA4Ig treatment suggests that CTLA-4 is needed for the induction and or maintenance of tolerance. ..
- Chambers C, Sullivan T, Allison J. Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells. Immunity. 1997;7:885-95 pubmed..These results demonstrate that CD4+ T cells initiate the phenotype in the CTLA-4(-/-) mice. Further, these results suggest that the role of CTLA-4 in peripheral CD4+ versus CD8+ T cell homeostasis is distinct. ..
- Chang T, Jabs C, Sobel R, Kuchroo V, Sharpe A. Studies in B7-deficient mice reveal a critical role for B7 costimulation in both induction and effector phases of experimental autoimmune encephalomyelitis. J Exp Med. 1999;190:733-40 pubmed
- Jacobs T, Graefe S, Niknafs S, Gaworski I, Fleischer B. Murine malaria is exacerbated by CTLA-4 blockade. J Immunol. 2002;169:2323-9 pubmedCytolytic T lymphocyte-associated Ag-4 (CD152) is a negatively regulating molecule, which is primarily expressed on T cells following their activation...
- Oosterwegel M, Mandelbrot D, Boyd S, Lorsbach R, Jarrett D, Abbas A, et al. The role of CTLA-4 in regulating Th2 differentiation. J Immunol. 1999;163:2634-9 pubmed..Thus, the B7-CD28/CTLA-4 pathway plays a critical role in regulating Th2 differentiation in two ways: CD28 promotes Th2 differentiation while CTLA-4 limits Th2 differentiation. ..
- van Berkel M, Schrijver E, Hofhuis F, Sharpe A, Coyle A, Broeren C, et al. ICOS contributes to T cell expansion in CTLA-4 deficient mice. J Immunol. 2005;175:182-8 pubmed..These results indicate that ICOS is not only important for T cell effector function but also contributes to the expansion phase of a T cell response in the presence of CD28 signaling. ..
- Stumpf M, Zhou X, Chikuma S, Bluestone J. Tyrosine 201 of the cytoplasmic tail of CTLA-4 critically affects T regulatory cell suppressive function. Eur J Immunol. 2014;44:1737-46 pubmed publisher..These data suggest that effects associated with and mediated through Tyr201 of CTLA-4s intracellular domain are critical for Treg-cell function. ..
- Muth S, Schütze K, Schild H, Probst H. Release of dendritic cells from cognate CD4+ T-cell recognition results in impaired peripheral tolerance and fatal cytotoxic T-cell mediated autoimmunity. Proc Natl Acad Sci U S A. 2012;109:9059-64 pubmed publisher..Consequently, mice in which interactions between DC and CD4(+) T cells are not possible develop spontaneous and fatal cytotoxic T lymphocyte-mediated autoimmunity. ..
- Katz G, Pobezinsky L, Jeurling S, Shinzawa M, Van Laethem F, Singer A. T cell receptor stimulation impairs IL-7 receptor signaling by inducing expression of the microRNA miR-17 to target Janus kinase 1. Sci Signal. 2014;7:ra83 pubmed publisher..Thus, this study identifies a molecular mechanism by which TCR engagement acutely disrupts IL-7 signaling. ..