Review Article

CD28: A New Drug Target for Immune Disease

Author(s): Sijing Xia, Qin Chen* and Bing Niu*

Volume 21, Issue 6, 2020

Page: [589 - 598] Pages: 10

DOI: 10.2174/1389450120666191114102830

Price: $65


Background: CD28, a cell surface glycoprotein receptor, predominantly expressed on activated T cells, belongs to the Ig superfamily and provides a critical co-stimulatory signal. CTLA-4 has sequence homology to CD28, and is expressed on T cells after activation. It provides an inhibition signal coordinated with CD28 to regulate T cell activation. Both of them regulate T cell proliferation and differentiation and play an important role in the immune response pathway in vivo.

Objective: We studied the special role of different structural sites of CD28 in producing costimulatory signals.

Methods: We reviewed the relevant literature, mainly regarding the structure of CD28 to clarify its biological function, and its role in the immune response.

Results: In recent years, increasingly attention has been paid to CD28, which is considered as a key therapeutic target for many modern diseases, especially some immune diseases.

Conclusion: In this paper, we mainly introduce the structure of CD28 and its related biological functions, as well as the application of costimulatory pathways targeting CD28 in disease treatment.

Keywords: CD28, CTLA-4, T cell activation, ligand, immune-responses, costimulation, human disease.

Graphical Abstract
Hansen, J.A.; Martin, P.J.; Nowinski, R.C. Monoclonal antibodies identifying a novel T-Cell antigen and Ia antigens of human lymphocytes. Immunogenetics, 1980, 10(1-4), 247-260.
Aruffo, A.; Seed, B. Molecular cloning of a CD28 cDNA by a high-efficiency COS cell expression system. Proc. Natl. Acad. Sci. USA, 1987, 84(23), 8573-8577.
[] [PMID: 2825196]
Evans, E.J.; Esnouf, R.M.; Manso-Sancho, R. Crystal structure of a soluble CD28-Fab complex. Nat. Immunol., 2005, 6(3), 271-279.
[] [PMID: 15696168]
Castan, J.; Tenner-Racz, K.; Racz, P.; Fleischer, B.; Bröker, B.M. Accumulation of CTLA-4 expressing T lymphocytes in the germinal centres of human lymphoid tissues. Immunology, 1997, 90(2), 265-271.
[] [PMID: 9135556]
Brunet, J.F.; Denizot, F.; Luciani, M.F. A new member of the immunoglobulin superfamily--CTLA-4. Nature, 1987, 328(6127), 267-270.
[] [PMID: 3496540]
Linsley, P.S.; Bradshaw, J.; Greene, J.; Peach, R.; Bennett, K.L.; Mittler, R.S. Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement. Immunity, 1996, 4(6), 535-543.
[] [PMID: 8673700]
Chikuma, S.; Abbas, A.K.; Bluestone, J.A. B7-independent inhibition of T cells by CTLA-4. J. Immunol., 2005, 175(1), 177-181.
[] [PMID: 15972645]
Walunas, T.L.; Bakker, C.Y.; Bluestone, J.A. CTLA-4 ligation blocks CD28-dependent T cell activation. J. Exp. Med., 1996, 183(6), 2541-2550.
[] [PMID: 8676075]
Ward, F.J.; Dahal, L.N.; Khanolkar, R.C.; Shankar, S.P.; Barker, R.N. Targeting the alternatively spliced soluble isoform of CTLA-4: prospects for immunotherapy? Immunotherapy, 2014, 6(10), 1073-1084.
[] [PMID: 25428646]
Higashikawa, K.; Yagi, K.; Watanabe, K. 64Cu-DOTA-anti-CTLA-4 mAb enabled PET visualization of CTLA-4 on the T-cell infiltrating tumor tissues. PLoS One, 2014, 9(11)e109866
[] [PMID: 25365349]
Lenschow, D.J.; Walunas, T.L.; Bluestone, J.A. CD28/B7 system of T cell costimulation. Annu. Rev. Immunol., 1996, 14(14), 233-258.
[] [PMID: 8717514]
Chen, L.; Flies, D.B. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol., 2013, 13(4), 227-242.
[] [PMID: 23470321]
Klein Geltink, R.I.; O’Sullivan, D.; Corrado, M. Mitochondrial Priming by CD28. Cell, 2017, 171(2), 385-397.e11.
[] [PMID: 28919076]
Bour-Jordan, H.; Blueston, J.A. CD28 function: a balance of costimulatory and regulatory signals. J. Clin. Immunol., 2002, 22(1), 1-7.
[] [PMID: 11958588]
Yang, W.; Pan, W.; Chen, S. Dynamic regulation of CD28 conformation and signaling by charged lipids and ions. Nat. Struct. Mol. Biol., 2017, 24(12), 1081-1092.
[] [PMID: 29058713]
Teteloshvili, N.; Dekkema, G.; Boots, A.M. Involvement of MicroRNAs in the Aging-Related Decline of CD28 Expression by Human T Cells. Front. Immunol., 2018, 9, 1400.
[] [PMID: 29967621]
Vallejo, A.N. CD28 extinction in human T cells: altered functions and the program of T-cell senescence. Immunol. Rev., 2005, 205(1), 158-169.
[] [PMID: 15882352]
Balzano, C; Buonavista, N; Rouvier, E; Golstein, P. CTLA-4 and CD28: similar proteins, neighbouring genes International journal of cancer Supplement = Journal international du cancer Supplement 1992; 7:28
Carreno, B.M.; Collins, M. The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses. Annu. Rev. Immunol., 2002, 20(20), 29-53.
[] [PMID: 11861596]
Mitsuiki, N.; Schwab, C.; Grimbacher, B. What did we learn from CTLA-4 insufficiency on the human immune system? Immunol. Rev., 2019, 287(1), 33-49.
[] [PMID: 30565239]
Kariv, I.; Truneh, A.; Sweet, R.W. Analysis of the site of interaction of CD28 with its counter-receptors CD80 and CD86 and correlation with function. J. Immunol., 1996, 157(1), 29-38.
[PMID: 8683128]
Peach, R.J.; Bajorath, J.; Brady, W. Complementarity determining region 1 (CDR1)- and CDR3-analogous regions in CTLA-4 and CD28 determine the binding to B7-1. J. Exp. Med., 1994, 180(6), 2049-2058.
[] [PMID: 7964482]
Truneh, A.; Reddy, M.; Ryan, P. Differential recognition by CD28 of its cognate counter receptors CD80 (B7.1) and B70 (B7.2): analysis by site directed mutagenesis. Mol. Immunol., 1996, 33(3), 321-334.
[] [PMID: 8649453]
Sharpe, A.H.; Freeman, G.J. The B7-CD28 superfamily. Nat. Rev. Immunol., 2002, 2(2), 116-126.
[] [PMID: 11910893]
Greenwald, R.J.; Freeman, G.J.; Sharpe, A.H. The B7 family revisited. Annu. Rev. Immunol., 2005, 23, 515-548.
[] [PMID: 15771580]
Schneider, H.; Downey, J.; Smith, A. Reversal of the TCR stop signal by CTLA-4. Science, 2006, 313(5795), 1972-1975.
[] [PMID: 16931720]
Sanchez-Lockhart, M.; Rojas, A.V.; Fettis, M.M. T cell receptor signaling can directly enhance the avidity of CD28 ligand binding. PLoS One, 2014, 9(2)e89263
[] [PMID: 24586641]
Sadra, A.; Cinek, T.; Arellano, J.L.; Shi, J.; Truitt, K.E.; Imboden, J.B. Identification of tyrosine phosphorylation sites in the CD28 cytoplasmic domain and their role in the costimulation of Jurkat T cells. J. Immunol., 1999, 162(4), 1966-1973.
[PMID: 9973466]
Yang, W.C.; Ghiotto, M.; Barbarat, B.; Olive, D. The role of Tec protein-tyrosine kinase in T cell signaling. J. Biol. Chem., 1999, 274(2), 607-617.
[] [PMID: 9872994]
Fraser, J.D.; Irving, B.A.; Crabtree, G.R.; Weiss, A. Regulation of interleukin-2 gene enhancer activity by the T cell accessory molecule CD28. Science, 1991, 251(4991), 313-316.
[] [PMID: 1846244]
Huang, G.N.; Huso, D.L.; Bouyain, S. NFAT binding and regulation of T cell activation by the cytoplasmic scaffolding Homer proteins. Science, 2008, 319(5862), 476-481.
[] [PMID: 18218901]
Watanabe, M.; Nakajima, S.; Ohnuki, K. AP-1 is involved in ICOS gene expression downstream of TCR/CD28 and cytokine receptor signaling. Eur. J. Immunol., 2012, 42(7), 1850-1862.
[] [PMID: 22585681]
Kane, L.P.; Lin, J.; Weiss, A. It’s all Rel-ative: NF-kappaB and CD28 costimulation of T-cell activation. Trends Immunol., 2002, 23(8), 413-420.
[] [PMID: 12133805]
June, C.H.; Ledbetter, J.A.; Gillespie, M.M.; Lindsten, T.; Thompson, C.B. T-cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression. Mol. Cell. Biol., 1987, 7(12), 4472-4481.
[] [PMID: 2830495]
Esensten, J.H.; Helou, Y.A.; Chopra, G.; Weiss, A.; Bluestone, J.A. CD28 costimulation: from mechanism to therapy. Immunity, 2016, 44(5), 973-988.
[] [PMID: 27192564]
Tai, X.; Van Laethem, F.; Sharpe, A.H.; Singer, A. Induction of autoimmune disease in CTLA-4-/- mice depends on a specific CD28 motif that is required for in vivo costimulation. Proc. Natl. Acad. Sci. USA, 2007, 104(34), 13756-13761.
[] [PMID: 17702861]
Dodson, L.F.; Boomer, J.S.; Deppong, C.M. Targeted knock-in mice expressing mutations of CD28 reveal an essential pathway for costimulation. Mol. Cell. Biol., 2009, 29(13), 3710-3721.
[] [PMID: 19398586]
Harada, Y.; Tokushima, M.; Matsumoto, Y. Critical requirement for the membrane-proximal cytosolic tyrosine residue for CD28-mediated costimulation in vivo. J. Immunol., 2001, 166(6), 3797-3803.
[] [PMID: 11238622]
Friend, L.D.; Shah, D.D.; Deppong, C. A dose-dependent requirement for the proline motif of CD28 in cellular and humoral immunity revealed by a targeted knockin mutant. J. Exp. Med., 2006, 203(9), 2121-2133.
[] [PMID: 16908623]
Boomer, J.S.; Deppong, C.M.; Shah, D.D.; Bricker, T.L.; Green, J.M. Cutting edge: A double-mutant knockin of the CD28 YMNM and PYAP motifs reveals a critical role for the YMNM motif in regulation of T cell proliferation and Bcl-xL expression. J. Immunol., 2014, 192(8), 3465-3469.
[] [PMID: 24639356]
Masihi, K.N. Fighting infection using immunomodulatory agents. Expert Opin. Biol. Ther., 2001, 1(4), 641-653.
[] [PMID: 11727500]
Chen, Y.; Wood, K.J. Interleukin-23 and TH17 cells in transplantation immunity: does 23+17 equal rejection? Transplantation, 2007, 84(9), 1071-1074.
[] [PMID: 17998858]
Fan, K.; Wang, H.; Wei, H. Blockade of LIGHT/HVEM and B7/CD28 signaling facilitates long-term islet graft survival with development of allospecific tolerance. Transplantation, 2007, 84(6), 746-754.
[] [PMID: 17893608]
Newell, K.A.; Asare, A.; Kirk, A.D. Immune tolerance network st507 study group. identification of a b cell signature associated with renal transplant tolerance in humans. J. Clin. Invest., 2010, 120(6), 1836-1847.
[] [PMID: 20501946]
Bluestone, J.A. New perspectives of CD28-B7-mediated T cell costimulation. Immunity, 1995, 2(6), 555-559.
[] [PMID: 7540940]
Larsen, C.P.; Elwood, E.T.; Alexander, D.Z. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature, 1996, 381(6581), 434-438.
[] [PMID: 8632801]
Zizzo, G.; Gremese, E.; Ferraccioli, G. Abatacept in the treatment of psoriatic arthritis: biological and clinical profiles of the responders. Immunotherapy, 2018, 10(9), 807-821.
[] [PMID: 29737909]
Álvarez-Quiroga, C.; Abud-Mendoza, C.; Doníz-Padilla, L. CTLA-4-Ig therapy diminishes the frequency but enhances the function of Treg cells in patients with rheumatoid arthritis. J. Clin. Immunol., 2011, 31(4), 588-595.
[] [PMID: 21487894]
Mathews, D.V.; Dong, Y.; Higginbotham, L.B. CD122 signaling in CD8+ memory T cells drives costimulation-independent rejection. J. Clin. Invest., 2018, 128(10), 4557-4572.
[] [PMID: 30222140]
Maldini, C.R.; Ellis, G.I.; Riley, J.L. CAR T cells for infection, autoimmunity and allotransplantation. Nat. Rev. Immunol., 2018, 18(10), 605-616.
[] [PMID: 30046149]
Leach, D.R.; Krummel, M.F.; Allison, J.P. Enhancement of antitumor immunity by CTLA-4 blockade. Science, 1996, 271(5256), 1734-1736.
[] [PMID: 8596936]
Callahan, M.K.; Postow, M.A.; Wolchok, J.D.; Targeting, T. Targeting T cell co-receptors for cancer therapy. Immunity, 2016, 44(5), 1069-1078.
[] [PMID: 27192570]
Suwalska, K.; Pawlak, E.; Karabon, L. Association studies of CTLA-4, CD28, and ICOS gene polymorphisms with B-cell chronic lymphocytic leukemia in the Polish population. Hum. Immunol., 2008, 69(3), 193-201.
[] [PMID: 18396212]
Schwarzbich, M.A.; Witzens-Harig, M. Cellular immunotherapy in b-cell malignancy. Oncol. Res. Treat., 2017, 40(11), 674-681.
[] [PMID: 29065420]
Savoldo, B.; Ramos, C.A.; Liu, E. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J. Clin. Invest., 2011, 121(5), 1822-1826.
[] [PMID: 21540550]
Maher, J.; Brentjens, R.J.; Gunset, G.; Rivière, I.; Sadelain, M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta/CD28 receptor. Nat. Biotechnol., 2002, 20(1), 70-75.
[] [PMID: 11753365]
Suntharalingam, G.; Perry, M.R.; Ward, S. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N. Engl. J. Med., 2006, 355(10), 1018-1028.
[] [PMID: 16908486]
Lin, C.H.; Hünig, T. Efficient expansion of regulatory T cells in vitro and in vivo with a CD28 superagonist. Eur. J. Immunol., 2003, 33(3), 626-638.
[] [PMID: 12616483]
Hansel, T.T.; Kropshofer, H.; Singer, T.; Mitchell, J.A.; George, A.J.T. The safety and side effects of monoclonal antibodies. Nat. Rev. Drug Discov., 2010, 9(4), 325-338.
[] [PMID: 20305665]
Mayes, P.A.; Hance, K.W.; Hoos, A. The promise and challenges of immune agonist antibody development in cancer. Nat. Rev. Drug Discov., 2018, 17(7), 509-527.
[] [PMID: 29904196]
Tabares, P.; Berr, S.; Römer, P.S. Human regulatory T cells are selectively activated by low-dose application of the CD28 superagonist TGN1412/TAB08. Eur. J. Immunol., 2014, 44(4), 1225-1236.
[] [PMID: 24374661]
D’Cruz, D.P.; Khamashta, M.A.; Hughes, G.R. Systemic lupus erythematosus. Lancet, 2007, 369(9561), 587-596.
[] [PMID: 17307106]
Katsuyama, T.; Tsokos, G.C.; Moulton, V.R.; Aberrant, T.; Aberrant, T. Cell signaling and subsets in systemic lupus erythematosus. Front. Immunol., 2018, 9, 1088.
[] [PMID: 29868033]
Dong, G.C.; Chuang, P.H.; Chang, K.C. Blocking effect of an immuno-suppressive agent, cynarin, on CD28 of T-cell receptor. Pharm. Res., 2009, 26(2), 375-381.
[] [PMID: 18989760]
García-Cózar, F.J.; Molina, I.J.; Cuadrado, M.J.; Marubayashi, M.; Peña, J.; Santamaría, M. Defective B7 expression on antigen-presenting cells underlying T cell activation abnormalities in systemic lupus erythematosus (SLE) patients. Clin. Exp. Immunol., 1996, 104(1), 72-79.
[] [PMID: 8603537]
Huang, L.; Kong, Y.; Wang, J.; Sun, J.; Shi, Q.; Qiu, Y.H. Reducing progression of experimental lupus nephritis via inhibition of the B7/CD28 signaling pathway. Mol. Med. Rep., 2015, 12(3), 4187-4195.
[] [PMID: 26096149]
Visser, H.; le Cessie, S.; Vos, K.; Breedveld, F.C.; Hazes, J.M.W. How to diagnose rheumatoid arthritis early: a prediction model for persistent (erosive) arthritis. Arthritis Rheum., 2002, 46(2), 357-365.
[] [PMID: 11840437]
Fessler, J.; Husic, R.; Schwetz, V. Senescent t-cells promote bone loss in rheumatoid arthritis. Front. Immunol., 2018, 9, 95.
[] [PMID: 29472917]
Schmidt, D.; Martens, P.B.; Weyand, C.M.; Goronzy, J.J. The repertoire of CD4+ CD28- T cells in rheumatoid arthritis. Mol. Med., 1996, 2(5), 608-618.
[] [PMID: 8898376]
Salazar-Fontana, L.I.; Sanz, E.; Mérida, I. Cell surface CD28 levels define four CD4+ T cell subsets: abnormal expression in rheumatoid arthritis. Clin. Immunol., 2001, 99(2), 253-265.
[] [PMID: 11318597]
Solomon, D.H.; Karlson, E.W.; Rimm, E.B. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation, 2003, 107(9), 1303-1307.
[] [PMID: 12628952]
Mori, G.; D’Amelio, P.; Faccio, R.; Brunetti, G. The Interplay between the bone and the immune system. Clin. Dev. Immunol., 2013, 2013(4)720504
[] [PMID: 23935650]
Lewis, D.E.; Merched-Sauvage, M.; Goronzy, J.J.; Weyand, C.M.; Vallejo, A.N. Tumor necrosis factor-alpha and CD80 modulate CD28 expression through a similar mechanism of T-cell receptor-independent inhibition of transcription. J. Biol. Chem., 2004, 279(28), 29130-29138.
[] [PMID: 15128741]
Bryl, E.; Vallejo, A.N.; Matteson, E.L.; Witkowski, J.M.; Weyand, C.M.; Goronzy, J.J. Modulation of CD28 expression with anti-tumor necrosis factor alpha therapy in rheumatoid arthritis. Arthritis Rheum., 2005, 52(10), 2996-3003.
[] [PMID: 16200579]
Masoli, M.; Fabian, D.; Holt, S.; Beasley, R. Global initiative for asthma (gina) program. the global burden of asthma: executive summary of the gina dissemination committee report. Allergy, 2004, 59(5), 469-478.
[] [PMID: 15080825]
Gogishvili, T.; Lühder, F.; Kirstein, F. Interruption of CD28-mediated costimulation during allergen challenge protects mice from allergic airway disease. J. Allergy Clin. Immunol., 2012, 130(6), 1394-403.e4.
[] [PMID: 23102920]
Asai-Tajiri, Y.; Matsumoto, K.; Fukuyama, S.; Kan-O, K.; Nakano, T.; Tonai, K. Small interfering RNA against CD86 during allergen challenge blocks experimental allergic asthma. Respiratory Research, 2014, 15(1), 1-11.
Genovese, M.C.; Becker, J.C.; Schiff, M. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N. Engl. J. Med., 2005, 353(11), 1114-1123.
[] [PMID: 16162882]
Ruperto, N.; Pistorio, A.; Ravelli, A. Paediatric rheumatology international trials organisation (printo); pediatric rheumatology collaborative study group (prcsg). the paediatric rheumatology international trials organisation provisional criteria for the evaluation of response to therapy in juvenile dermatomyositis. Arthritis Care Res. (Hoboken), 2010, 62(11), 1533-1541.
[] [PMID: 20583105]
Orban, T.; Bundy, B.; Becker, D.J. Type 1 diabetes trialnet abatacept study group. co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet, 2011, 378(9789), 412-419.
[] [PMID: 21719096]
Orban, T.; Bundy, B.; Becker, D.J. Type 1 Diabetes TrialNet Abatacept Study Group. Costimulation modulation with abatacept in patients with recent-onset type 1 diabetes: follow-up 1 year after cessation of treatment. Diabetes Care, 2014, 37(4), 1069-1075.
[] [PMID: 24296850]
Lekpa, F.K.; Farrenq, V.; Canouï-Poitrine, F. Lack of efficacy of abatacept in axial spondylarthropathies refractory to tumor-necrosis-factor inhibition. Joint Bone Spine, 2012, 79(1), 47-50.
[] [PMID: 21497538]
Furie, R.; Nicholls, K.; Cheng, T.T. Efficacy and safety of abatacept in lupus nephritis: a twelve-month, randomized, double-blind study. Arthritis Rheumatol., 2014, 66(2), 379-389.
[] [PMID: 24504810]
Group, A.T. ACCESS trial group. treatment of lupus nephritis with abatacept: the abatacept and cyclophosphamide combination efficacy and safety study. Arthritis Rheumatol., 2014, 66(11), 3096-3104.
[] [PMID: 25403681]
Parulekar, A.D.; Boomer, J.S.; Patterson, B.M. A randomized controlled trial to evaluate inhibition of T-cell costimulation in allergen-induced airway inflammation. Am. J. Respir. Crit. Care Med., 2013, 187(5), 494-501.
[] [PMID: 23292882]
Sandborn, W.J.; Colombel, J.F.; Sands, B.E. Abatacept for Crohn’s disease and ulcerative colitis. Gastroenterology, 2012, 143(1), 62-69.e4.
[] [PMID: 22504093]
Klintmalm, G.B.; Feng, S.; Lake, J.R. Belatacept-based immunosuppression in de novo liver transplant recipients: 1-year experience from a phase II randomized study. Am. J. Transplant., 2014, 14(8), 1817-1827.
[] [PMID: 25041339]
Vincenti, F.; Larsen, C.; Durrbach, A. Belatacept Study Group. Costimulation blockade with belatacept in renal transplantation. N. Engl. J. Med., 2005, 353(8), 770-781.
[] [PMID: 16120857]
Schraven, B.; Kalinke, U. CD28 superagonists: what makes the difference in humans? Immunity, 2008, 28(5), 591-595.
[] [PMID: 18482560]
Hünig, T. The storm has cleared: lessons from the CD28 superagonist TGN1412 trial. Nat. Rev. Immunol., 2012, 12(5), 317-318.
[] [PMID: 22487653]

Rights & Permissions Print Export Cite as
© 2024 Bentham Science Publishers | Privacy Policy