DOI QR코드

DOI QR Code

Current Understanding of Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) Signaling in T-Cell Biology and Disease Therapy

  • Kim, Gil-Ran (Department of Life Science, College of Natural Sciences, Hanyang University) ;
  • Choi, Je-Min (Department of Life Science, College of Natural Sciences, Hanyang University)
  • Received : 2021.12.31
  • Accepted : 2022.05.02
  • Published : 2022.08.31

Abstract

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an immune checkpoint molecule that is mainly expressed on activated T cells and regulatory T (Treg) cells that inhibits T-cell activation and regulates immune homeostasis. Due to the crucial functions of CTLA-4 in T-cell biology, CTLA-4-targeted immunotherapies have been developed for autoimmune disease as well as cancers. CTLA-4 is known to compete with CD28 to interact with B7, but some studies have revealed that its downstream signaling is independent of its ligand interaction. As a signaling domain of CTLA-4, the tyrosine motif plays a role in inhibiting T-cell activation. Recently, the lysine motif has been shown to be required for the function of Treg cells, emphasizing the importance of CTLA-4 signaling. In this review, we summarize the current understanding of CTLA-4 biology and molecular signaling events and discuss strategies to target CTLA-4 signaling for immune modulation and disease therapy.

Keywords

Acknowledgement

This research was supported by grants from the Bio and Medical Technology Development Program (NRF-2017M3A9C8027972) and Basic Science Research Program (NRF-2019R1A2C3006155) of the National Research Foundation funded by the Korean government to J.-M.C.

References

  1. Banton, M.C., Inder, K.L., Valk, E., Rudd, C.E., and Schneider, H. (2014). Rab8 binding to immune cell-specific adaptor LAX facilitates formation of trans-Golgi network-proximal CTLA-4 vesicles for surface expression. Mol. Cell. Biol. 34, 1486-1499. https://doi.org/10.1128/MCB.01331-13
  2. Barnes, M.J., Griseri, T., Johnson, A.M., Young, W., Powrie, F., and Izcue, A. (2013). CTLA-4 promotes Foxp3 induction and regulatory T cell accumulation in the intestinal lamina propria. Mucosal Immunol. 6, 324-334. https://doi.org/10.1038/mi.2012.75
  3. Bradshaw, J.D., Lu, P., Leytze, G., Rodgers, J., Schieven, G.L., Bennett, K.L., Linsley, P.S., and Kurtz, S.E. (1997). Interaction of the cytoplasmic tail of CTLA-4 (CD152) with a clathrin-associated protein is negatively regulated by tyrosine phosphorylation. Biochemistry 36, 15975-15982. https://doi.org/10.1021/bi971762i
  4. Brunet, J.F., Denizot, F., Luciani, M.F., Roux-Dosseto, M., Suzan, M., Mattei, M.G., and Golstein, P. (1987). A new member of the immunoglobulin superfamily--CTLA-4. Nature 328, 267-270. https://doi.org/10.1038/328267a0
  5. Chambers, C.A., Sullivan, T.J., and Allison, J.P. (1997). Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells. Immunity 7, 885-895. https://doi.org/10.1016/S1074-7613(00)80406-9
  6. Chao, G., Li, X., Ji, Y., Zhu, Y., Li, N., Zhang, N., Feng, Z., and Niu, M. (2018). CTLA-4 regulates T follicular regulatory cell differentiation and participates in intestinal damage caused by spontaneous autoimmunity. Biochem. Biophys. Res. Commun. 505, 865-871. https://doi.org/10.1016/j.bbrc.2018.09.182
  7. Chikuma, S., Abbas, A.K., and Bluestone, J.A. (2005). B7-independent inhibition of T cells by CTLA-4. J. Immunol. 175, 177-181. https://doi.org/10.4049/jimmunol.175.1.177
  8. Chikuma, S., Murakami, M., Tanaka, K., and Uede, T. (2000). Janus kinase 2 is associated with a box 1-like motif and phosphorylates a critical tyrosine residue in the cytoplasmic region of cytotoxic T lymphocyte associated molecule-4. J. Cell. Biochem. 78, 241-250.
  9. Choi, J.M., Ahn, M.H., Chae, W.J., Jung, Y.G., Park, J.C., Song, H.M., Kim, Y.E., Shin, J.A., Park, C.S., Park, J.W., et al. (2006). Intranasal delivery of the cytoplasmic domain of CTLA-4 using a novel protein transduction domain prevents allergic inflammation. Nat. Med. 12, 574-579. https://doi.org/10.1038/nm1385
  10. Choi, J.M., Kim, S.H., Shin, J.H., Gibson, T., Yoon, B.S., Lee, D.H., Lee, S.K., Bothwell, A.L., Lim, J.S., and Lee, S.K. (2008). Transduction of the cytoplasmic domain of CTLA-4 inhibits TcR-specific activation signals and prevents collagen-induced arthritis. Proc. Natl. Acad. Sci. U. S. A. 105, 19875-19880. https://doi.org/10.1073/pnas.0805198105
  11. Chuang, E., Alegre, M.L., Duckett, C.S., Noel, P.J., Vander Heiden, M.G., and Thompson, C.B. (1997). Interaction of CTLA-4 with the clathrin-associated protein AP50 results in ligand-independent endocytosis that limits cell surface expression. J. Immunol. 159, 144-151. https://doi.org/10.4049/jimmunol.159.1.144
  12. Chuang, E., Fisher, T.S., Morgan, R.W., Robbins, M.D., Duerr, J.M., Vander Heiden, M.G., Gardner, J.P., Hambor, J.E., Neveu, M.J., and Thompson, C.B. (2000). The CD28 and CTLA-4 receptors associate with the serine/threonine phosphatase PP2A. Immunity 13, 313-322. https://doi.org/10.1016/S1074-7613(00)00031-5
  13. Chuang, E., Lee, K.M., Robbins, M.D., Duerr, J.M., Alegre, M.L., Hambor, J.E., Neveu, M.J., Bluestone, J.A., and Thompson, C.B. (1999). Regulation of cytotoxic T lymphocyte-associated molecule-4 by Src kinases. J. Immunol. 162, 1270-1277. https://doi.org/10.4049/jimmunol.162.3.1270
  14. Contardi, E., Palmisano, G.L., Tazzari, P.L., Martelli, A.M., Fala, F., Fabbi, M., Kato, T., Lucarelli, E., Donati, D., Polito, L., et al. (2005). CTLA-4 is constitutively expressed on tumor cells and can trigger apoptosis upon ligand interaction. Int. J. Cancer 117, 538-550. https://doi.org/10.1002/ijc.21155
  15. Curran, M.A., Montalvo, W., Yagita, H., and Allison, J.P. (2010). PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc. Natl. Acad. Sci. U. S. A. 107, 4275-4280. https://doi.org/10.1073/pnas.0915174107
  16. Fallarino, F., Grohmann, U., Hwang, K.W., Orabona, C., Vacca, C., Bianchi, R., Belladonna, M.L., Fioretti, M.C., Alegre, M.L., and Puccetti, P. (2003). Modulation of tryptophan catabolism by regulatory T cells. Nat. Immunol. 4, 1206-1212. https://doi.org/10.1038/ni1003
  17. Genovese, M.C., Becker, J.C., Schiff, M., Luggen, M., Sherrer, Y., Kremer, J., Birbara, C., Box, J., Natarajan, K., Nuamah, I., et al. (2005). Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N. Engl. J. Med. 353, 1114-1123. https://doi.org/10.1056/NEJMoa050524
  18. Glatigny, S., Hollbacher, B., Motley, S.J., Tan, C., Hundhausen, C., Buckner, J.H., Smilek, D., Khoury, S.J., Ding, L., Qin, T., et al. (2019). Abatacept targets T follicular helper and regulatory T cells, disrupting molecular pathways that regulate their proliferation and maintenance. J. Immunol. 202, 1373-1382.
  19. Guntermann, C. and Alexander, D.R. (2002). CTLA-4 suppresses proximal TCR signaling in resting human CD4(+) T cells by inhibiting ZAP-70 Tyr(319) phosphorylation: a potential role for tyrosine phosphatases. J. Immunol. 168, 4420-4429. https://doi.org/10.4049/jimmunol.168.9.4420
  20. Hodi, F.S., O'Day, S.J., McDermott, D.F., Weber, R.W., Sosman, J.A., Haanen, J.B., Gonzalez, R., Robert, C., Schadendorf, D., Hassel, J.C., et al. (2010). Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711-723. https://doi.org/10.1056/NEJMoa1003466
  21. Hu, H., Rudd, C.E., and 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, 573-578. https://doi.org/10.1006/bbrc.2001.5814
  22. Jiang, Y., Li, Y., and Zhu, B. (2015). T-cell exhaustion in the tumor microenvironment. Cell Death Dis. 6, e1792.
  23. Khattri, R., Auger, J.A., Griffin, M.D., Sharpe, A.H., and Bluestone, J.A. (1999). Lymphoproliferative disorder in CTLA-4 knockout mice is characterized by CD28-regulated activation of Th2 responses. J. Immunol. 162, 5784-5791. https://doi.org/10.4049/jimmunol.162.10.5784
  24. Khoury, S.J., Rochon, J., Ding, L., Byron, M., Ryker, K., Tosta, P., Gao, W., Freedman, M.S., Arnold, D.L., Sayre, P.H., et al. (2017). ACCLAIM: a randomized trial of abatacept (CTLA4-Ig) for relapsing-remitting multiple sclerosis. Mult. Scler. 23, 686-695. https://doi.org/10.1177/1352458516662727
  25. Kim, G.R., Kim, W.J., Lim, S., Lee, H.G., Koo, J.H., Nam, K.H., Kim, S.M., Park, S.D., and Choi, J.M. (2021a). In vivo induction of regulatory T cells via CTLA-4 signaling peptide to control autoimmune encephalomyelitis and prevent disease relapse. Adv. Sci. (Weinh.) 8, 2004973.
  26. Kim, H.K., Jeong, M.G., and Hwang, E.S. (2021b). Post-translational modifications in transcription factors that determine T helper cell differentiation. Mol. Cells 44, 318-327. https://doi.org/10.14348/molcells.2021.0057
  27. Klocke, K., Sakaguchi, S., Holmdahl, R., and Wing, K. (2016). Induction of autoimmune disease by deletion of CTLA-4 in mice in adulthood. Proc. Natl. Acad. Sci. U. S. A. 113, E2383-E2392.
  28. Kong, K.F., Fu, G., Zhang, Y., Yokosuka, T., Casas, J., Canonigo-Balancio, A.J., Becart, S., Kim, G., Yates, J.R., 3rd, Kronenberg, M., et al. (2014). Protein kinase C-eta controls CTLA-4-mediated regulatory T cell function. Nat. Immunol. 15, 465-472.
  29. Kozik, P., Francis, R.W., Seaman, M.N.J., and Robinson, M.S. (2010). A screen for endocytic motifs. Traffic 11, 843-855. https://doi.org/10.1111/j.1600-0854.2010.01056.x
  30. Krummel, M.F. and Allison, J.P. (1995). CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J. Exp. Med1. 82, 459-465. https://doi.org/10.1084/jem.182.2.459
  31. Larsen, C.P., Pearson, T.C., Adams, A.B., Tso, P., Shirasugi, N., Strobert, E., Anderson, D., Cowan, S., Price, K., Naemura, J., et al. (2005). Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am. J. Transplant. 5, 443-453. https://doi.org/10.1111/j.1600-6143.2005.00749.x
  32. Latek, R., Fleener, C., Lamian, V., Kulbokas, E., 3rd, Davis, P.M., Suchard, S.J., Curran, M., Vincenti, F., and Townsend, R. (2009). Assessment of belatacept-mediated costimulation blockade through evaluation of CD80/86-receptor saturation. Transplantation 87, 926-933. https://doi.org/10.1097/TP.0b013e31819b5a58
  33. Lim, S., Ho Sohn, J., Koo, J.H., Park, J.W., and Choi, J.M. (2017). dNP2-ctCTLA-4 inhibits German cockroach extract-induced allergic airway inflammation and hyper-responsiveness via inhibition of Th2 responses. Exp. Mol. Med. 49, e362.
  34. Lim, S., Kim, W.J., Kim, Y.H., Lee, S., Koo, J.H., Lee, J.A., Yoon, H., Kim, D.H., Park, H.J., Kim, H.M., et al. (2015). dNP2 is a blood-brain barrier-permeable peptide enabling ctCTLA-4 protein delivery to ameliorate experimental autoimmune encephalomyelitis. Nat. Commun. 6, 8244.
  35. Lim, S., Kirkiles-Smith, N.C., Pober, J.S., Bothwell, A.L.M., and Choi, J.M. (2018). Regulation of human T cell responses by dNP2-ctCTLA-4 inhibits human skin and microvessel graft rejection. Biomaterials 183, 128-138. https://doi.org/10.1016/j.biomaterials.2018.08.049
  36. Ling, V., Wu, P.W., Finnerty, H.F., Sharpe, A.H., Gray, G.S., and Collins, M. (1999). Complete sequence determination of the mouse and human CTLA4 gene loci: cross-species DNA sequence similarity beyond exon borders. Genomics 60, 341-355. https://doi.org/10.1006/geno.1999.5930
  37. Lingel, H., Wissing, J., Arra, A., Schanze, D., Lienenklaus, S., Klawonn, F., Pierau, M., Zenker, M., Jansch, L., and Brunner-Weinzierl, M.C. (2017). CTLA-4-mediated posttranslational modifications direct cytotoxic T-lymphocyte differentiation. Cell Death Differ. 24, 1739-1749. https://doi.org/10.1038/cdd.2017.102
  38. Linsley, P.S., Bradshaw, J., Greene, J., Peach, R., Bennett, K.L., and Mittler, R.S. (1996). Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement. Immunity 4, 535-543. https://doi.org/10.1016/S1074-7613(00)80480-X
  39. Linsley, P.S., Brady, W., Urnes, M., Grosmaire, L.S., Damle, N.K., and Ledbetter, J.A. (1991). CTLA-4 is a second receptor for the B cell activation antigen B7. J. Exp. Med. 174, 561-569. https://doi.org/10.1084/jem.174.3.561
  40. Linsley, P.S., Clark, E.A., and Ledbetter, J.A. (1990). T-cell antigen CD28 mediates adhesion with B cells by interacting with activation antigen B7/BB-1. Proc. Natl. Acad. Sci. U. S. A. 87, 5031-5035. https://doi.org/10.1073/pnas.87.13.5031
  41. Linsley, P.S., Greene, J.L., Brady, W., Bajorath, J., Ledbetter, J.A., and Peach, R. (1994). Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1, 793-801. https://doi.org/10.1016/S1074-7613(94)80021-9
  42. Lo, B., Zhang, K., Lu, W., Zheng, L., Zhang, Q., Kanellopoulou, C., Zhang, Y., Liu, Z., Fritz, J.M., Marsh, R., et al. (2015). AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science 349, 436-440.
  43. Marengere, L.E., Waterhouse, P., Duncan, G.S., Mittrucker, H.W., Feng, G.S., and Mak, T.W. (1996). Regulation of T cell receptor signaling by tyrosine phosphatase SYP association with CTLA-4. Science 272, 1170-1173. https://doi.org/10.1126/science.272.5265.1170
  44. Mead, K.I., Zheng, Y., Manzotti, C.N., Perry, L.C., Liu, M.K., Burke, F., Powner, D.J., Wakelam, M.J., and Sansom, D.M. (2005). Exocytosis of CTLA-4 is dependent on phospholipase D and ADP ribosylation factor-1 and stimulated during activation of regulatory T cells. J. Immunol. 174, 4803-4811. https://doi.org/10.4049/jimmunol.174.8.4803
  45. Mease, P.J., Gottlieb, A.B., van der Heijde, D., FitzGerald, O., Johnsen, A., Nys, M., Banerjee, S., and Gladman, D.D. (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, 1550-1558. https://doi.org/10.1136/annrheumdis-2016-210724
  46. Miyatake, S., Nakaseko, C., Umemori, H., Yamamoto, T., and Saito, T. (1998). Src family tyrosine kinases associate with and phosphorylate CTLA-4 (CD152). Biochem. Biophys. Res. Commun. 249, 444-448. https://doi.org/10.1006/bbrc.1998.9191
  47. Olsson, C., Riesbeck, K., Dohlsten, M., and Michaelsson, E. (1999). CTLA-4 ligation suppresses CD28-induced NF-kappaB and AP-1 activity in mouse T cell blasts. J. Biol. Chem. 274, 14400-14405. https://doi.org/10.1074/jbc.274.20.14400
  48. Parulekar, A.D., Boomer, J.S., Patterson, B.M., Yin-Declue, H., Deppong, C.M., Wilson, B.S., Jarjour, N.N., Castro, M., and Green, J.M. (2013). A randomized controlled trial to evaluate inhibition of T-cell costimulation in allergen-induced airway inflammation. Am. J. Respir. Crit. Care Med. 187, 494-501. https://doi.org/10.1164/rccm.201207-1205OC
  49. Paterson, A.M., Lovitch, S.B., Sage, P.T., Juneja, V.R., Lee, Y., Trombley, J.D., Arancibia-Carcamo, C.V., Sobel, R.A., Rudensky, A.Y., Kuchroo, V.K., et al. (2015). Deletion of CTLA-4 on regulatory T cells during adulthood leads to resistance to autoimmunity. J. Exp. Med. 212, 1603-1621. https://doi.org/10.1084/jem.20141030
  50. Pedros, C., Canonigo-Balancio, A.J., Kong, K.F., and Altman, A. (2017). Requirement of Treg-intrinsic CTLA4/PKCeta signaling pathway for suppressing tumor immunity. JCI Insight 2, e95692.
  51. Qureshi, O.S., Kaur, S., Hou, T.Z., Jeffery, L.E., Poulter, N.S., Briggs, Z., Kenefeck, R., Willox, A.K., Royle, S.J., Rappoport, J.Z., et al. (2012). Constitutive clathrin-mediated endocytosis of CTLA-4 persists during T cell activation. J. Biol. Chem. 287, 9429-9440. https://doi.org/10.1074/jbc.M111.304329
  52. Qureshi, O.S., Zheng, Y., Nakamura, K., Attridge, K., Manzotti, C., Schmidt, E.M., Baker, J., Jeffery, L.E., Kaur, S., Briggs, Z., et al. (2011). Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332, 600-603. https://doi.org/10.1126/science.1202947
  53. Read, S., Greenwald, R., Izcue, A., Robinson, N., Mandelbrot, D., Francisco, L., Sharpe, A.H., and Powrie, F. (2006). Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo. J. Immunol. 177, 4376-4383. https://doi.org/10.4049/jimmunol.177.7.4376
  54. Read, S., Malmstrom, V., and 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, 295-302. https://doi.org/10.1084/jem.192.2.295
  55. Sage, P.T., Paterson, A.M., Lovitch, S.B., and Sharpe, A.H. (2014). The coinhibitory receptor CTLA-4 controls B cell responses by modulating T follicular helper, T follicular regulatory, and T regulatory cells. Immunity 41, 1026-1039. https://doi.org/10.1016/j.immuni.2014.12.005
  56. Sandborn, W.J., Colombel, J.F., Sands, B.E., Rutgeerts, P., Targan, S.R., Panaccione, R., Bressler, B., Geboes, K., Schreiber, S., Aranda, R., et al. (2012). Abatacept for Crohn's disease and ulcerative colitis. Gastroenterology 143, 62-69.e4. https://doi.org/10.1053/j.gastro.2012.04.010
  57. Schneider, H., Downey, J., Smith, A., Zinselmeyer, B.H., Rush, C., Brewer, J.M., Wei, B., Hogg, N., Garside, P., and Rudd, C.E. (2006). Reversal of the TCR stop signal by CTLA-4. Science 313, 1972-1975. https://doi.org/10.1126/science.1131078
  58. Schneider, H., Martin, M., Agarraberes, F.A., Yin, L., Rapoport, I., Kirchhausen, T., and Rudd, C.E. (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, 1868-1879. https://doi.org/10.4049/jimmunol.163.4.1868
  59. Schneider, H., Prasad, K.V., Shoelson, S.E., and Rudd, C.E. (1995). CTLA-4 binding to the lipid kinase phosphatidylinositol 3-kinase in T cells. J. Exp. Med. 181, 351-355. https://doi.org/10.1084/jem.181.1.351
  60. Schneider, H. and Rudd, C.E. (2014). Diverse mechanisms regulate the surface expression of immunotherapeutic target ctla-4. Front. Immunol. 5, 619.
  61. Schneider, H., Smith, X., Liu, H., Bismuth, G., and Rudd, C.E. (2008). CTLA-4 disrupts ZAP70 microcluster formation with reduced T cell/APC dwell times and calcium mobilization. Eur. J. Immunol. 38, 40-47. https://doi.org/10.1002/eji.200737423
  62. Schubert, D., Bode, C., Kenefeck, R., Hou, T.Z., Wing, J.B., Kennedy, A., Bulashevska, A., Petersen, B.S., Schaffer, A.A., Gruning, B.A., et al. (2014). Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat. Med. 20, 1410-1416. https://doi.org/10.1038/nm.3746
  63. Seidel, J.A., Otsuka, A., and Kabashima, K. (2018). Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations. Front. Oncol. 8, 86.
  64. Serwas, N.K., Hoeger, B., Ardy, R.C., Stulz, S.V., Sui, Z., Memaran, N., Meeths, M., Krolo, A., Yuce Petronczki, O., Pfajfer, L., et al. (2019). Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis. Nat. Commun. 10, 3106.
  65. Shiratori, T., Miyatake, S., Ohno, H., Nakaseko, C., Isono, K., Bonifacino, J.S., and Saito, T. (1997). Tyrosine phosphorylation controls internalization of CTLA-4 by regulating its interaction with clathrin-associated adaptor complex AP-2. Immunity 6, 583-589. https://doi.org/10.1016/S1074-7613(00)80346-5
  66. Srahna, M., Van Grunsven, L.A., Remacle, J.E., and Vandenberghe, P. (2006). CTLA-4 interacts with STAT5 and inhibits STAT5-mediated transcription. Immunology 117, 396-401. https://doi.org/10.1111/j.1365-2567.2005.02313.x
  67. Stumpf, M., Zhou, X., and Bluestone, J.A. (2013). The B7-independent isoform of CTLA-4 functions to regulate autoimmune diabetes. J. Immunol. 190, 961-969. https://doi.org/10.4049/jimmunol.1201362
  68. Stumpf, M., Zhou, X., Chikuma, S., and Bluestone, J.A. (2014). Tyrosine 201 of the cytoplasmic tail of CTLA-4 critically affects T regulatory cell suppressive function. Eur. J. Immunol. 44, 1737-1746. https://doi.org/10.1002/eji.201343891
  69. Szentpetery, A., Heffernan, E., Gogarty, M., Mellerick, L., McCormack, J., Haroon, M., Elmamoun, M., Gallagher, P., Kelly, G., Fabre, A., et al. (2017). Abatacept reduces synovial regulatory T-cell expression in patients with psoriatic arthritis. Arthritis Res. Ther. 19, 158.
  70. Takahashi, T., Tagami, T., Yamazaki, S., Uede, T., Shimizu, J., Sakaguchi, N., Mak, T.W., and Sakaguchi, S. (2000). Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 192, 303-310. https://doi.org/10.1084/jem.192.2.303
  71. Teft, W.A., Chau, T.A., and Madrenas, J. (2009). Structure-Function analysis of the CTLA-4 interaction with PP2A. BMC Immunol. 10, 23.
  72. Ueda, H., Howson, J.M., Esposito, L., Heward, J., Snook, H., Chamberlain, G., Rainbow, D.B., Hunter, K.M., Smith, A.N., Di Genova, G., et al. (2003). Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423, 506-511. https://doi.org/10.1038/nature01621
  73. Valk, E., Rudd, C.E., and Schneider, H. (2008). CTLA-4 trafficking and surface expression. Trends Immunol. 29, 272-279. https://doi.org/10.1016/j.it.2008.02.011
  74. Verhagen, J., Gabrysova, L., Shepard, E.R., and Wraith, D.C. (2014). Ctla-4 modulates the differentiation of inducible Foxp3+ Treg cells but IL-10 mediates their function in experimental autoimmune encephalomyelitis. PLoS One 9, e108023.
  75. Vijayakrishnan, L., Slavik, J.M., Illes, Z., Greenwald, R.J., Rainbow, D., Greve, B., Peterson, L.B., Hafler, D.A., Freeman, G.J., Sharpe, A.H., et al. (2004). An autoimmune disease-associated CTLA-4 splice variant lacking the B7 binding domain signals negatively in T cells. Immunity 20, 563-575. https://doi.org/10.1016/S1074-7613(04)00110-4
  76. Walunas, T.L., Lenschow, D.J., Bakker, C.Y., Linsley, P.S., Freeman, G.J., Green, J.M., Thompson, C.B., and Bluestone, J.A. (1994). CTLA-4 can function as a negative regulator of T cell activation. Immunity 1, 405-413. https://doi.org/10.1016/1074-7613(94)90071-X
  77. Wang, C.J., Heuts, F., Ovcinnikovs, V., Wardzinski, L., Bowers, C., Schmidt, E.M., Kogimtzis, A., Kenefeck, R., Sansom, D.M., and Walker, L.S. (2015). CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement. Proc. Natl. Acad. Sci. U. S. A.1 12, 524-529.
  78. Waterhouse, P., Penninger, J.M., Timms, E., Wakeham, A., Shahinian, A., Lee, K.P., Thompson, C.B., Griesser, H., and Mak, T.W. (1995). Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270, 985-988. https://doi.org/10.1126/science.270.5238.985
  79. Watkins, B., Qayed, M., McCracken, C., Bratrude, B., Betz, K., Suessmuth, Y., Yu, A., Sinclair, S., Furlan, S., Bosinger, S., et al. (2021). Phase II trial of costimulation blockade with abatacept for prevention of acute GVHD. J. Clin. Oncol. 39, 1865-1877. https://doi.org/10.1200/JCO.20.01086
  80. Wei, S.C., Sharma, R., Anang, N.A.S., Levine, J.H., Zhao, Y., Mancuso, J.J., Setty, M., Sharma, P., Wang, J., Pe'er, D., et al. (2019). Negative co-stimulation constrains T cell differentiation by imposing boundaries on possible cell states. Immunity 50, 1084-1098.e10. https://doi.org/10.1016/j.immuni.2019.03.004
  81. Wing, K., Onishi, Y., Prieto-Martin, P., Yamaguchi, T., Miyara, M., Fehervari, Z., Nomura, T., and Sakaguchi, S. (2008). CTLA-4 control over Foxp3+ regulatory T cell function. Science 322, 271-275. https://doi.org/10.1126/science.1160062
  82. Yang, Y., Li, X., Ma, Z., Wang, C., Yang, Q., Byrne-Steele, M., Hong, R., Min, Q., Zhou, G., Cheng, Y., et al. (2021). CTLA-4 expression by B-1a B cells is essential for immune tolerance. Nat. Commun. 12, 525.
  83. Yi, L.A., Hajialiasgar, S., and Chuang, E. (2004). Tyrosine-mediated inhibitory signals contribute to CTLA-4 function in vivo. Int. Immunol. 16, 539-547. https://doi.org/10.1093/intimm/dxh055
  84. Zhang, H., Dutta, P., Liu, J., Sabri, N., Song, Y., Li, W.X., and Li, J. (2019). Tumour cell-intrinsic CTLA4 regulates PD-L1 expression in non-small cell lung cancer. J. Cell. Mol. Med. 23, 535-542. https://doi.org/10.1111/jcmm.13956
  85. Zhang, Y. and Allison, J.P. (1997). Interaction of CTLA-4 with AP50, a clathrin-coated pit adaptor protein. Proc. Natl. Acad. Sci. U. S. A. 94, 9273-9278. https://doi.org/10.1073/pnas.94.17.9273
  86. Zheng, S.G., Wang, J.H., Stohl, W., Kim, K.S., Gray, J.D., and Horwitz, D.A. (2006). TGF-beta requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4+CD25+ regulatory cells. J. Immunol. 176, 3321-3329. https://doi.org/10.4049/jimmunol.176.6.3321