Abstract
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is an inhibitory receptor belonging to the CD28 immunoglobulin subfamily, expressed primarily by T-cells. Its ligands, CD80 and CD86, are typically found on the surface of antigen-presenting cells and can either bind CD28 or CTLA-4, resulting in a costimulatory or a co-inhibitory response, respectively. Because of its dampening effect, CTLA-4 is a crucial regulator of T-cell homeostasis and self-tolerance. The mechanisms by which CTLA-4 exerts its inhibitory function can be categorized as either cell-intrinsic (affects the CTLA-4 expressing T-cell) or cell-extrinsic (affects secondary cells). Research from the last decade has shown that CTLA-4 mainly acts in a cell-extrinsic manner via its competition with CD28, CTLA-4-mediated trans-endocytosis of CD80 and CD86, and its direct tolerogenic effects on the interacting cell. Nonetheless, intrinsic CTLA-4 signaling has been implicated in T-cell motility and the regulation of CTLA-4 its subcellular localization amongst others. CTLA-4 is well recognized as a key immune checkpoint and has gained significant momentum as a therapeutic target in the field of autoimmunity and cancer. In this chapter, we describe the role of costimulation in immune response induction as well as the main mechanisms by which CTLA-4 can inhibit this process.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Aaes TL et al (2016) Vaccination with necroptotic cancer cells induces efficient anti-tumor immunity. Cell Rep 15(2):274–287. https://doi.org/10.1016/J.CELREP.2016.03.037. Cell Press
Abrams JR et al (1999) CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris. J Clin Investig 103(9):1243–1252. https://doi.org/10.1172/JCI5857
Acuto O, Michel F (2003) CD28-mediated co-stimulation: a quantitative support for TCR signalling. Nat Rev Immunol 3(12):939–951. https://doi.org/10.1038/nri1248. Nature Publishing Group
Adams AB, Ford ML, Larsen CP (2016) Costimulation blockade in autoimmunity and transplantation: the CD28 pathway HHS public access. J Immunol 197(6):2045–2050. https://doi.org/10.4049/jimmunol.1601135
Alissafi T et al (2017) Tregs restrain dendritic cell autophagy to ameliorate autoimmunity. J Clin Investig 127(7):2789–2804. https://doi.org/10.1172/jci92079
Apetoh L et al (2007) The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol Rev 220(1):47–59. https://doi.org/10.1111/j.1600-065X.2007.00573.x
Appleman LJ, Boussiotis VA (2003) T cell anergy and costimulation. Immunol Rev 192(1):161–180. https://doi.org/10.1034/j.1600-065x.2003.00009.x. Wiley (10.1111)
Arra A et al (2017) The differentiation and plasticity of Tc17 cells are regulated by CTLA-4-mediated effects on STATs. Oncoimmunology 6(2):e1273300. https://doi.org/10.1080/2162402x.2016.1273300. Taylor & Francis
Baroja ML et al (2002) Inhibition of CTLA-4 function by the regulatory subunit of serine/threonine phosphatase 2A. J Immunol 168(10):5070–5078. https://doi.org/10.4049/jimmunol.168.10.5070
BarquÃn-GarcÃa A et al (2019) New oncologic emergencies: what is there to know about immunotherapy and its potential side effects? Eur J Intern Med. https://doi.org/10.1016/j.ejim.2019.05.020
Bochkov VN et al (2010) Generation and biological activities of oxidized phospholipids. Antioxid Redox Signal 12(8):1009–1059. https://doi.org/10.1089/ars.2009.2597
Boomer JS, Green JM (2010) An enigmatic tail of CD28 signaling. Cold Spring Harb Perspect Biol 2(8):a002436. https://doi.org/10.1101/cshperspect.a002436. Cold Spring Harbor Laboratory Press
Borrie AE, Maleki Vareki S (2018) T lymphocyte-based cancer immunotherapeutics. Int Rev Cell Mol Biol 341:201–276. https://doi.org/10.1016/BS.IRCMB.2018.05.010. Academic
Bourque J, Hawiger D (2018) Immunomodulatory bonds of the partnership between dendritic cells and T cells. Crit Rev Immunol 38(5):379–401. https://doi.org/10.1615/critrevimmunol.2018026790. NIH Public Access
Bretscher PA (1999) A two-step, two-signal model for the primary activation of precursor helper T cells. Proc Natl Acad Sci 96(1):185–190. https://doi.org/10.1073/pnas.96.1.185
Bretscher P, Cohn M (1970) A theory of self-nonself discrimination 169(1964)
Brunet J-F et al (1987) A new member of the immunoglobulin superfamily—CTLA-4. Nature 328(6127):267–270. https://doi.org/10.1038/328267a0
Buchbinder EI, Desai A (2015) CTLA-4 and PD-1 pathways similarities, differences, and implications of their inhibition. https://doi.org/10.1097/COC.0000000000000239
Calvo CR, Amsen D, Kruisbeek AM (1997) Cytotoxic T lymphocyte antigen 4 (CTLA-4) interferes with extracellular signal-regulated kinase (ERK) and Jun NH2-terminal kinase (JNK) activation, but does not affect phosphorylation of T cell receptor zeta and ZAP70. J Exp Med 186(10):1645–1653. https://doi.org/10.1084/jem.186.10.1645. Rockefeller University Press
Cao W et al (2014) Oxidized lipids block antigen cross-presentation by dendritic cells in cancer. J Immunol 192(6):2920–2931. https://doi.org/10.4049/jimmunol.1302801
Carreno BM, Collins M (2002) The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses. Annu Rev Immunol 20:29–53. https://doi.org/10.1146/annurev.immunol.20.091101.091806
Chambers CA et al (2001) CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol 19(1):565–594. https://doi.org/10.1146/annurev.immunol.19.1.565. Annual Reviews 4139 El Camino Way, P.O. Box 10139, Palo Alto, CA 94303-0139, USA
Chambers CA, Allison JP (1997) ‘Co-stimulation in T cell responses. Curr Opin Immunol 9(3):396–404. https://doi.org/10.1016/S0952-7915(97)80087-8. Elsevier Current Trends
Chen L, Flies DB (2013) Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol 13(4):227–242. https://doi.org/10.1038/nri3405
Collins AV et al (2002) The interaction properties of costimulatory molecules revisited. Immunity 17(2):201–210. https://doi.org/10.1016/S1074-7613(02)00362-X
Coyle AJ et al (2000) The CD28-related molecule ICOS is required for effective T cell-dependent immune responses. Immunity 13(1):95–105. https://doi.org/10.1016/S1074-7613(00)00011-X. Cell Press
Crimeen-Irwin B et al (2005) Failure of immune homeostasis – the consequences of under and over reactivity. Curr Drug Targets. Immune, Endocr Metab Disord 5(4):413–422. http://www.ncbi.nlm.nih.gov/pubmed/16375694. Accessed 21 July 2019
Croft M (2003) Costimulation of T cells by OX40, 4-1BB, and CD27. Cytokine Growth Factor Rev 14(3–4):265–273. https://doi.org/10.1016/S1359-6101(03)00025-X. Pergamon
Dixon SJ et al (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. https://doi.org/10.1016/j.cell.2012.03.042
Dower NA et al (2000) RasGRP is essential for mouse thymocyte differentiation and TCR signaling. Nat Immunol 1(4):317–321. https://doi.org/10.1038/79766
Dunn GP, Old LJ, Schreiber RD (2004) The three Es of cancer immunoediting. Annu Rev Immunol 22(1):329–360. https://doi.org/10.1146/annurev.immunol.22.012703.104803. Annual Reviews
Elgueta R et al (2009) Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev 229(1):152–172. https://doi.org/10.1111/j.1600-065x.2009.00782.x. NIH Public Access
Engelhardt JJ, Sullivan TJ, Allison JP (2006) CTLA-4 overexpression Inhibits T cell responses through a CD28-B7-dependent mechanism. J Immunol 177:1052–1061. https://doi.org/10.4049/jimmunol.177.2.1052
Esensten JH et al (2016) CD28 costimulation: from mechanism to therapy. Immunity 44(5):973–988. https://doi.org/10.1016/j.immuni.2016.04.020
Fallarino F et al (2003) Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol 4(12):1206–1212. https://doi.org/10.1038/ni1003. Nature Publishing Group
Flies DB et al (2014) Coinhibitory receptor PD-1H preferentially suppresses CD4+ T cell–mediated immunity. J Clin Investig 124(5):1966–1975. https://doi.org/10.1172/JCI74589.American Society for Clinical Investigation
Freeman GJ (2004) Murine B7-2, an alternative CTLA4 counter-receptor that costimulates T cell proliferation and interleukin 2 production. J Exp Med 178:2185–2192. https://doi.org/10.1084/jem.178.6.2185
Galluzzi L et al (2018) Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. Cell Death Differ. https://doi.org/10.1038/s41418-017-0012-4
Gao Q et al (2019) A cycle involving HMGB1, IFN-γ and dendritic cells plays a putative role in anti-tumor immunity. Cell Immunol 343:103850. https://doi.org/10.1016/J.CELLIMM.2018.08.011. Academic
Gavrieli M, Murphy KM (2006) ‘Association of Grb-2 and PI3K p85 with phosphotyrosile peptides derived from BTLA. Biochem Biophys Res Commun 345(4):1440–1445. https://doi.org/10.1016/J.BBRC.2006.05.036. Academic
Ghahremanloo A et al (2019) Recent advances in the clinical development of immune checkpoint blockade therapy. Cell Oncol. https://doi.org/10.1007/s13402-019-00456-w
Golden EB, Apetoh L (2015) Radiotherapy and immunogenic cell death. Semin Radiat Oncol 25(1):11–17. https://doi.org/10.1016/j.semradonc.2014.07.005. Elsevier
Haining WN, Weiss SA (2018) c-Maf in CD4+ T cells: it’s all about context. Nat Immunol 19(5):429–431. https://doi.org/10.1038/s41590-018-0087-1. Nature Publishing Group
Halpert MM et al (2016) Dendritic cell-secreted cytotoxic T-lymphocyte-associated protein-4 regulates the T-cell response by downmodulating bystander surface B7. Stem Cells Dev 25(10):774–787. https://doi.org/10.1089/scd.2016.0009
Hangauer MJ et al (2017) Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 551(7679):247–250. https://doi.org/10.1038/nature24297. Nature Publishing Group
Hassannia B et al (2018) Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma. J Clin Investig 128:3341–3355. https://doi.org/10.1172/JCI99032
Hirahara K, Nakayama T (2016) CD4+ T-cell subsets in inflammatory diseases: beyond the Th1/Th2 paradigm. Int Immunol 28(4):163–171. https://doi.org/10.1093/intimm/dxw006. Narnia
Hodi FS et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723. https://doi.org/10.1056/NEJMoa1003466
Hu H, Rudd CE, Schneider H (2001) Src kinases Fyn and Lck facilitate the accumulation of phosphorylated CTLA-4 and its association with PI-3 kinase in intracellular compartments of T-cells. Biochem Biophys Res Commun 288(3):573–578. https://doi.org/10.1006/BBRC.2001.5814. Academic
Hutloff A et al (1999) ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397(6716):263–266. https://doi.org/10.1038/16717. Nature Publishing Group
Ikemizu S et al (2000) Structure and dimerization of a soluble form of B7-1 transfecting B7-1 into murine tumors (Chen et al or from using anti-CTLA-4 antibodies to block CTLA-4 interactions with B7-1 and, immunity. Townsend and Allison). https://www.cell.com/action/showPdf?pii=S1074-7613%2800%2980158-2. Accessed 11 July 2019
Isakov N, Altman A (2002) Protein kinase Cθ in T cell activation. Annu Rev Immunol 20(1):761–794. https://doi.org/10.1146/annurev.immunol.20.100301.064807. Annual Reviews 4139 El Camino Way, P.O. Box 10139, Palo Alto, CA 94303-0139, USA
Jain N et al (2010) Dual function of CTLA-4 in regulatory T cells and conventional T cells to prevent multiorgan autoimmunity. Proc Natl Acad Sci 107(4):1524–1528. https://doi.org/10.1073/pnas.0910341107
Jenkins MK et al (1987) T-cell unresponsiveness in vivo and in vitro: fine specificity of induction and molecular characterization of the unresponsive state. Immunol Rev 95:113–135. http://www.ncbi.nlm.nih.gov/pubmed/2437012. Accessed 12 May 2019
June CH et al (1987) T-cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression. Mol Cell Biol 7(12):4472–4481. American Society for Microbiology (ASM). https://doi.org/10.1128/mcb.7.12.4472
Jung M et al (2019) Iron as a central player and promising target in cancer progression. Int J Mol Sci 20(2):1–18. https://doi.org/10.3390/ijms20020273
Kaur S, Qureshi OS, Sansom DM (2013) Comparison of the intracellular trafficking itinerary of CTLA-4 orthologues. PLoS ONE 8(4):e60903. https://doi.org/10.1371/journal.pone.0060903. Boudinot P (ed) Public Library of Science
Kepp O et al (2014) Consensus guidelines for the detection of immunogenic cell death. OncoImmunology 3(9):1–19. https://doi.org/10.4161/21624011.2014.955691
Khailaie S et al (2018) Characterization of CTLA4 trafficking and implications for its function. Biophys J 115(7):1330–1343. https://doi.org/10.1016/J.BPJ.2018.08.020. Cell Press
Korman AJ, Peggs KS, Allison JP (2006) Checkpoint blockade in cancer immunotherapy. Adv Immunol 90:297–339. https://doi.org/10.1016/s0065-2776(06)90008-x
Kroczek RA, Mages HW, Hutloff A (2004) Emerging paradigms of T-cell co-stimulation. Curr Opin Immunol 16(3):321–327. https://doi.org/10.1016/j.coi.2004.03.002
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):459–465. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2192127/pdf/je1822459.pdf. Accessed 10 June 2019
Krummey SM et al (2014) High CTLA-4 expression on Th17 cells results in increased sensitivity to CTLA-4 coinhibition and resistance to belatacept. Am J Transplant: Off J Am Soc Transplant Am Soc Transpl Surg 14(3):607–614. http://www.ncbi.nlm.nih.gov/pubmed/24730049. Accessed 17 Sept 2019. NIH Public Access
Kuemmerle-Deschner JB, Benseler SM (2008) Abatacept in difficult-to-treat juvenile idiopathic arthritis. Targets Ther, Biologics, pp 865–874
Kumar P, Bhattacharya P, Prabhakar BS (2018) A comprehensive review on the role of co-signaling receptors and Treg homeostasis in autoimmunity and tumor immunity. J Autoimmun 95:77–99. https://doi.org/10.1016/J.JAUT.2018.08.007. Academic
Lafferty K, Cunningham A (1975) A new analysis of allogeneic interactions. Aust J Exp Biol Med Sci 53(1):27–42. https://doi.org/10.1038/icb.1975.3. Wiley (10.1111)
Lafferty KJ, Woolnough J (1977) The origin and mechanism of the allograft reaction. Immunol Rev 35(1):231–262. https://doi.org/10.1111/j.1600-065x.1977.tb00241.x. Wiley (10.1111)
Lafferty KJ et al (1978) Immunological induction of T lymphocytes: role of antigen and the lymphocyte costimulator. Blood Cells 4(3):395–406. http://www.ncbi.nlm.nih.gov/pubmed/95670. Accessed 9 June 2019
Laurent S et al (2010) CTLA-4 is expressed by human monocyte-derived dendritic cells and regulates their functions. Hum Immunol 71(10):934–941. https://doi.org/10.1016/j.humimm.2010.07.007
Leach DR, Krummel MF, Allison JP (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science 271(5256):1734–1736. https://doi.org/10.1126/science.271.5256.1734
Lee K-M et al (1998) Molecular basis of T cell inactivation by CTLA-4. Science 282(5397):2263–2266. https://doi.org/10.1126/science.282.5397.2263. American Association for the Advancement of Science
Lindsten T et al (1993) Characterization of CTLA-4 structure and expression on human T cells. J Immunol 151(7)3489–3799. http://www.jimmunol.org/content/151/7/3489. Accessed 13 July 2019. Baltimore, Md.: 1950
Lingel H et al (2017) CTLA-4-mediated posttranslational modifications direct cytotoxic T-lymphocyte differentiation. Cell Death Differ 24(10):1739–1749. https://doi.org/10.1038/cdd.2017.102. Nature Publishing Group
Linsley PS, Clark EA, Ledbetter JA (1990) T-cell antigen CD28 mediates adhesion with B cells by interacting with activation antigen B7/BB-1. Proc Natl Acad Sci 87(13):5031–5035. https://doi.org/10.1073/pnas.87.13.5031
Linsley PS et al (1991) CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 174(3):561–569. https://doi.org/10.1084/jem.174.3.561. The Rockefeller University Press
Linsley PS et al (1992) Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science 257(5071):792–795. https://doi.org/10.1126/science.1496399. American Association for the Advancement of Science, New York, N.Y.
Linsley PS et al (1995) Binding stoichiometry of the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4). J Biol Chem 270(25):15417–15424. https://doi.org/10.1074/jbc.270.25.15417
Mages HW et al (2000) ‘Molecular cloning and characterization of murine ICOS and identification of B7h as ICOS ligand. Eur J Immunol 30(4):1040–1047. https://doi.org/10.1002/(SICI)1521-4141(200004)30:4%3c1040:AID-IMMU1040%3e3.0.CO;2-6. Wiley
Magistrelli G et al (1999) A soluble form of CTLA-4 generated by alternative splicing is expressed by nonstimulated human T cells. Eur J Immunol 29(11):3596–3602. https://doi.org/10.1002/(SICI)1521-4141(199911)29:11%3c3596:AID-IMMU3596%3e3.0.CO;2-Y
Mak TW et al (2014) Primer to the immune response. https://www.worldcat.org/title/primer-to-the-immune-response/oclc/900161289. Accessed 3 Sept 2019
Marengère LE et al (1996) Regulation of T cell receptor signaling by tyrosine phosphatase SYP association with CTLA-4. Science 272(5265):1170–1173. https://doi.org/10.1126/science.272.5265.1170. New York, N.Y.
Matheu MP et al (2015) Imaging regulatory T cell dynamics and CTLA4-mediated suppression of T cell priming. Nat Commun 6:6219. https://doi.org/10.1038/ncomms7219
Mease PJ et al (2017) Efficacy and safety of abatacept, a T-cell modulator, in a randomised, double-blind, placebo-controlled, phase III study in psoriatic arthritis. Ann Rheum Dis 76(9):1550–1558. https://doi.org/10.1136/annrheumdis-2016-210724
Mellman I, Coukos G, Dranoff G (2011) Cancer immunotherapy comes of age. Nature 480(7378):480–489. https://doi.org/10.1038/nature10673
Metzler WJ et al (1997) Solution structure of human CTLA-4 and delineation of a CD80/CD86 binding site conserved in CD28. Nat Struct Biol 4(7):527–531. http://www.ncbi.nlm.nih.gov/pubmed/9228944. Accessed 14 July 2019
Mir MA (2015) Introduction to costimulation and costimulatory molecules. Developing Costimulatory Molecules for Immunotherapy of Diseases. https://doi.org/10.1016/B978-0-12-802585-7.00001-7
Moreland LW et al (2002) Costimulatory blockade in patients with rheumatoid arthritis: a pilot, dose-finding, double-blind, placebo-controlled clinical trial evaluating CTLA-4Ig and LEA29Y eighty-five days after the first infusion. Arthritis Rheum 46(6):1470–1479. https://doi.org/10.1002/art.10294
Motzer RJ et al (2018) Nivolumab plus Ipilimumab versus sunitinib in advanced renal-cell carcinoma. New Engl J Med 378(14):1277–1290. https://doi.org/10.1056/NEJMoa1712126. Massachusetts Medical Society
Mueller DL (1989) Do tolerant T cells exist? Nature 339(6225):513–514. https://doi.org/10.1038/339513a0. Nature Publishing Group
Munn DH, Sharma MD, Mellor AL (2004) Ligation of B7-1/B7-2 by human CD4+ T cells triggers indoleamine 2,3-dioxygenase activity in dendritic cells. J Immunol 172(7):4100–4110. https://doi.org/10.4049/jimmunol.172.7.4100. Baltimore, Md.: 1950
Murphy K, Weaver C (2017) Janeway’s immunobiology, 9th edn
Murphy KM, Nelson CA, Šedý JR (2006) Balancing co-stimulation and inhibition with BTLA and HVEM. Nat Rev Immunol 6(9):671–681. https://doi.org/10.1038/nri1917. Nature Publishing Group
NIH US National Library of Medicine (2019) Home - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/home. Accessed 24 July 2019
O’Donnell JS, Teng MWL, Smyth MJ (2019) Cancer immunoediting and resistance to T cell-based immunotherapy. Nat Rev Clin Oncol 16(3):151–167. https://doi.org/10.1038/s41571-018-0142-8
Obeid M et al (2007) Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 13(1):54–61. https://doi.org/10.1038/nm1523
Oh-hora M, Rao A (2009) The calcium/NFAT pathway: role in development and function of regulatory T cells. Microbes Infect 11(5):612–619. https://doi.org/10.1016/j.micinf.2009.04.008. NIH Public Access
Oskolkova OV et al (2010) Oxidized phospholipids are more potent antagonists of lipopolysaccharide than inducers of inflammation. J Immunol 185(12):7706–7712. https://doi.org/10.4049/jimmunol.0903594
Ovcinnikovs V et al (2019) CTLA-4–mediated transendocytosis of costimulatory molecules primarily targets migratory dendritic cells. Sci Immunol 4(35):eaaw0902. https://doi.org/10.1126/sciimmunol.aaw0902
Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 252–264. https://doi.org/10.1038/nrc3239
Parry RV et al (2005) CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 25(21):9543–9553. https://doi.org/10.1128/mcb.25.21.9543-9553.2005. American Society for Microbiology (ASM)
Pentcheva-Hoang T et al (2004) B7-1 and B7-2 selectively recruit CTLA-4 and CD28 to the immunological synapse. Immunity 21(3):401–413. https://doi.org/10.1016/J.IMMUNI.2004.06.017. Cell Press
Poleszczuk J, Enderling H (2018) The optimal radiation dose to induce robust systemic anti-tumor immunity. Int J Mol Sci 19(11). https://doi.org/10.3390/ijms19113377
Qureshi OS et al (2011) Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332(6029):600–603. https://doi.org/10.1126/science.1202947
Rao A, Luo C, Hogan PG (2002) Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol 15(1):707–747. https://doi.org/10.1146/annurev.immunol.15.1.707
Ravetch JV, Lanier LL (2000) Immune inhibitory receptors. Science 290(5489):84–89. https://doi.org/10.1126/science.290.5489.84. American Association for the Advancement of Science, New York, N.Y.
Read S, Malmström V, Powrie F (2000) Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med 192(2):295–302. https://doi.org/10.1084/jem.192.2.295. Rockefeller University Press
Ren J et al (2017) The RIP3-RIP1-NF-kB signaling axis is dispensable for necroptotic cells to elicit cross-priming of CD8+ T cells. Cell Mol Immunol 14(7):639–642. https://doi.org/10.1038/cmi.2017.31. Nature Publishing Group
Rowshanravan B, Halliday N, Sansom DM (2018) CTLA-4: a moving target in immunotherapy. Blood 131(1):58–67. https://doi.org/10.1182/blood-2017-06-741033. Europe PMC Funders
Rudd CE (2008) The reverse stop-signal model for CTLA4 function. Nat Rev Immunol 8:153–160. www.nature.com/reviews/immunol. Accessed 26 July 2019
Rudd CE, Schneider H (2003) Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling. Nat Rev Immunol 3(7):544–556. https://doi.org/10.1038/nri1131. Nature Publishing Group
Rudd CE, Taylor A, Schneider H (2009) CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev 229(1):12–26. https://doi.org/10.1111/j.1600-065x.2009.00770.x. Europe PMC Funders
Ruperto N et al (2008) Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial. The Lancet 372(9636):383–391. https://doi.org/10.1016/S0140-6736(08)60998-8
Saito T, Yokosuka T, Hashimoto-Tane A (2010) Dynamic regulation of T cell activation and co-stimulation through TCR-microclusters. FEBS Lett 584(24):4865–4871. https://doi.org/10.1016/j.febslet.2010.11.036. Wiley
Sakaguchi S et al (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151–1164. http://www.jimmunol.org/content/155/3/1151. Accessed 21 July 2019
Sanchez-Lockhart M et al (2014) T cell receptor signaling can directly enhance the avidity of CD28 ligand binding. PLoS ONE 9(2):89263. https://doi.org/10.1371/journal.pone.0089263
Saverino D et al (2010) The soluble CTLA-4 receptor and its role in autoimmune diseases: an update. Autoimmun Highlights 1(2):73–81. https://doi.org/10.1007/s13317-010-0011-7
Schneider H, Rudd CE (2000) Tyrosine phosphatase SHP-2 binding to CTLA-4: absence of direct YVKM/YFIP motif recognition. Biochem Biophys Res Commun 269(1):279–283. https://doi.org/10.1006/BBRC.2000.2234. Academic
Schneider H et al (1999) Cytolytic T lymphocyte-associated antigen-4 and the TCR zeta/CD3 complex, but not CD28, interact with clathrin adaptor complexes AP-1 and AP-2. J Immunol 163(4):1868–1879. http://www.ncbi.nlm.nih.gov/pubmed/10438921. Accessed 12 July 2019. Baltimore, Md.: 1950
Schneider H et al (2001) A regulatory role for cytoplasmic YVKM motif in CTLA-4 inhibition of TCR signaling. Eur J Immunol 31(7):2042–2050. https://doi.org/10.1002/1521-4141(200107)31:7%3c2042:AID-IMMU2042%3e3.0.CO;2-D. Wiley
Schneider H et al (2006) Reversal of the TCR stop signal by CTLA-4. Science 313(5795):1972–1975. https://doi.org/10.1126/science.1131078
Schneider H, Valk E et al (2008a) CTLA-4 activation of phosphatidylinositol 3-kinase (PI 3-K) and protein kinase B (PKB/AKT) sustains T-cell anergy without cell death. PLoS ONE 3(12):e3842. https://doi.org/10.1371/journal.pone.0003842. Wölfl S (ed) Public Library of Science
Schneider H, Smith X et al (2008b) CTLA-4 disrupts ZAP70 microcluster formation with reduced T cell/APC dwell times and calcium mobilization. Eur J Immunol 38(1):40–47. https://doi.org/10.1002/eji.200737423. Wiley
Schubert D et al (2014) Autosomal-dominant immune dysregulation syndrome in humans with CTLA4 mutations Europe PMC funders group. Nat Med 20(12):1410–1416. https://doi.org/10.1038/nm.3746
Schwartz RH (1990) A cell culture model for T lymphocyte clonal anergy. Science 248(4961):1349–1356. http://www.ncbi.nlm.nih.gov/pubmed/2113314. Accessed 12 May 2019. New York, N.Y.
Sedy JR et al (2005) B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nat Immunol 6(1):90–98. https://doi.org/10.1038/ni1144. Nature Publishing Group
Shapiro VS et al (1997) CD28 mediates transcriptional upregulation of the interleukin-2 (IL-2) promoter through a composite element containing the CD28RE and NF-IL-2B AP-1 sites. Mol Cell Biol 17(7):4051–4058. https://doi.org/10.1128/mcb.17.7.4051. American Society for Microbiology (ASM)
Sharpe AH, Freeman GJ (2002) The B7-CD28 superfamily. Nat Rev Immunol 2:116. https://doi.org/10.1038/nri727
Shinohara T et al (1994) Structure and chromosomal localization of the human PD-1 gene (PDCD1). Genomics 23(3):704–706. https://doi.org/10.1006/GENO.1994.1562. Academic
Shiratori T et al (1997) Tyrosine phosphorylation controls internalization of CTLA-4 by regulating its interaction with clathrin-associated adaptor complex AP-2. Immunity 6(5):583–589. https://doi.org/10.1016/S1074-7613(00)80346-5
Simons KH et al (2019) T cell co-stimulation and co-inhibition in cardiovascular disease: a double-edged sword. Nat Rev Cardiol 16(6):325–343. https://doi.org/10.1038/s41569-019-0164-7
Sinclair NRSC (1990) Commentary I: how many signals are enough? Cell Immunol 130(1):204–212. https://doi.org/10.1016/0008-8749(90)90174-P. Academic
Sinclair NRSC, Anderson CC (1996) Co-stimulation and co-inhibition: Equal partners in regulation. Scand J Immunol 597–603. https://doi.org/10.1046/j.1365-3083.1996.d01-267.x. Wiley (10.1111)
Stephen B, Hajjar J (2018) Overview of basic immunology and translational relevance for clinical investigators. Adv Exp Med Biol 995:1–41. https://doi.org/10.1007/978-3-030-02505-2_1. Springer, Cham
Sturgill ER, Redmond WL (2017) TNFR agonists: a review of current biologics targeting OX40, 4-1BB, CD27, and GITR. Am J Hematol/Oncol 13(11):4–15. www.ajho.com. Accessed 10 June 2019
Sugár IP et al (2017) Multiscale modeling of complex formation and CD80 depletion during immune synapse development. Biophys J Biophys Soc 112(5):997–1009. https://doi.org/10.1016/j.bpj.2016.12.052
Sun H et al (2014) Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4 HHS public access. Science 345(6204):1623–1627. https://doi.org/10.1126/science.1255904
Takahashi T et al (2000a) Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 192(2):303–310. https://doi.org/10.1084/jem.192.2.303. Rockefeller University Press
Takahashi T et al (2000b) Immunologic self-tolerance maintained by CD25+CD4+regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 192(2):303–309. https://doi.org/10.1084/jem.192.2.303
Teft WA, Kirchhof MG, Madrenas J (2006) A molecular perspective of CTLA-4 function. https://doi.org/10.1146/annurev.immunol.24.021605.090535
Thompson Emma L, Masteller CB, Chuang E, Mullen AC (2000) Structural analysis of CTLA-4 function in vivo. J Immunol 164:5319–5327. https://doi.org/10.4049/jimmunol.164.10.5319
Tivol EA et al (1995a) Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3(5):541–547. https://doi.org/10.1016/1074-7613(95)90125-6
Tivol EA et al (1995b) Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. https://www.cell.com/immunity/pdf/1074-7613(95)90125-6.pdf. Accessed 10 June 2019
Topalian SL, Weiner GJ, Pardoll DM (2011) Cancer immunotherapy comes of age. J Clin Oncol 29(36):4828–4836. https://doi.org/10.1200/JCO.2011.38.0899
Van Der Merwe PA, Davis SJ (2003) Molecular interactions mediating T cell antigen recognition. Annu Rev Immunol 21:659–684. https://doi.org/10.1146/annurev.immunol.21.120601.141036
Verma N et al (2017) Immune deficiency and autoimmunity in patients with CTLA-4 (CD152) mutations. Clin Exp Immunol 190:1–7. https://doi.org/10.1111/cei.12997
Vincenti F et al (2010) A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (benefit study). Am J Transplant 10(3):535–546. https://doi.org/10.1111/j.1600-6143.2009.03005.x
Walker LSK (2017) EFIS lecture: understanding the CTLA-4 checkpoint in the maintenance of immune homeostasis. Immunol Lett 184:43–50. https://doi.org/10.1016/j.imlet.2017.02.007. Elsevier B.V.
Walker LSK, Sansom DM (2015) Confusing signals: recent progress in CTLA-4 biology. Trends Immunol 36(2):63–70. https://doi.org/10.1016/j.it.2014.12.001. Elsevier
Wang XB et al (2011) CTLA4 is expressed on mature dendritic cells derived from human monocytes and influences their maturation and antigen presentation. BMC Immunol 12(1):21. https://doi.org/10.1186/1471-2172-12-21
Ward SG (1996) CD28: a signalling perspective. Biochem J 318:361–377. https://doi.org/10.1042/bj3180361. Portland Press Limited
Waterhouse P et al (1995) Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270(5238):985–988. https://doi.org/10.1126/science.270.5238.985. New York, N.Y.
Watts TH (2004) TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol 23(1):23–68. https://doi.org/10.1146/annurev.immunol.23.021704.115839
Wherry EJ et al (2007) Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27(4):670–684. https://doi.org/10.1016/j.immuni.2007.09.006
Wing K et al (2008) CTLA-4 control over Foxp3+ regulatory T cell function. Science 322:271–275. https://doi.org/10.1126/science.1164164
Yamaguchi T et al (2013) Construction of self-recognizing regulatory T cells from conventional T cells by controlling CTLA-4 and IL-2 expression. Proc Natl Acad Sci USA 110(23):E2116–E2125. https://doi.org/10.1073/pnas.1307185110
Yang W et al (2017) Dynamic regulation of CD28 conformation and signaling by charged lipids and ions. Nat Struct Mol Biol 24:1081. https://doi.org/10.1038/nsmb.3489
Yokosuka T et al (2010) Spatiotemporal basis of CTLA-4 costimulatory molecule-mediated negative regulation of T cell activation. Immunity 33(3):326–339. https://doi.org/10.1016/j.immuni.2010.09.006
Yoshinaga SK et al (1999) T-cell co-stimulation through B7RP-1 and ICOS. Nature 402(6763):827–832. https://doi.org/10.1038/45582. Nature Publishing Group
Zhang, YI, Allison JP (1997) Interaction of CTLA-4 with AP50, a clathrin-coated pit adaptor protein. Immunology. www.pnas.org. Accessed 12 July 2019
Zhang Q, Vignali DAA (2016) Co-stimulatory and Co-inhibitory pathways in autoimmunity. Immunity 44:1034–1051. https://doi.org/10.1016/j.immuni.2016.04.017
Zou W, Chen L (2008) Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol 8:467–477. https://doi.org/10.1038/nri2326
Author information
Authors and Affiliations
Corresponding authors
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2020 Springer Nature Singapore Pte Ltd.
About this chapter
Cite this chapter
Van Coillie, S., Wiernicki, B., Xu, J. (2020). Molecular and Cellular Functions of CTLA-4. In: Xu, J. (eds) Regulation of Cancer Immune Checkpoints. Advances in Experimental Medicine and Biology, vol 1248. Springer, Singapore. https://doi.org/10.1007/978-981-15-3266-5_2
Download citation
DOI: https://doi.org/10.1007/978-981-15-3266-5_2
Published:
Publisher Name: Springer, Singapore
Print ISBN: 978-981-15-3265-8
Online ISBN: 978-981-15-3266-5
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)