Immune inhibitory proteins and their pathogenic and therapeutic implications in autoimmunity and autoimmune hepatitis

References

• Czaja AJ. Transitioning from idiopathic to explainable autoimmune hepatitis. Dig Dis Sci. 2015;60:2881–2900.
   PubMed Web of Science ®Google Scholar
• Mieli-Vergani G, Vergani D, Czaja AJ. Autoimmune hepatitis. Nat Rev Dis Primers. 2018;4:18017.
   PubMed Web of Science ®Google Scholar
• Donaldson PT, Doherty DG, Hayllar KM, et al. Susceptibility to autoimmune chronic active hepatitis: human leukocyte antigens DR4 and A1-B8-DR3 are independent risk factors. Hepatology. 1991;13:701–706.
   PubMed Web of Science ®Google Scholar
• Czaja AJ, Carpenter HA, Santrach PJ, et al. Significance of HLA DR4 in type 1 autoimmune hepatitis. Gastroenterology. 1993;105:1502–1507.
   PubMed Web of Science ®Google Scholar
• Strettell MD, Donaldson PT, Thomson LJ, et al. Allelic basis for HLA-encoded susceptibility to type 1 autoimmune hepatitis. Gastroenterology. 1997;112:2028–2035.
   PubMed Web of Science ®Google Scholar
• Czaja AJ, Donaldson PT. Genetic susceptibilities for immune expression and liver cell injury in autoimmune hepatitis. Immunol Rev. 2000;174:250–259.
   PubMed Web of Science ®Google Scholar
• Czaja AJ, Strettell MD, Thomson LJ, et al. Associations between alleles of the major histocompatibility complex and type 1 autoimmune hepatitis. Hepatology. 1997;25:317–323.
   PubMed Web of Science ®Google Scholar
• Cookson S, Constantini PK, Clare M, et al. Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis. Hepatology. 1999;30:851–856.
   PubMed Web of Science ®Google Scholar
• Czaja AJ. Genetic factors affecting the occurrence, clinical phenotype, and outcome of autoimmune hepatitis. Clin Gastroenterol Hepatol. 2008;6:379–388.
   PubMed Web of Science ®Google Scholar
• de Boer YS, van Gerven NM, Zwiers A, et al. Genome-wide association study identifies variants associated with autoimmune hepatitis type 1. Gastroenterology. 2014;147:443–452.
   PubMed Web of Science ®Google Scholar
• van Gerven NM, de Boer YS, Zwiers A, et al. HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1. Genes Immun. 2015;16:247–252.
   PubMed Web of Science ®Google Scholar
• Javierre BM, Hernando H, Ballestar E. Environmental triggers and epigenetic deregulation in autoimmune disease. Discov Med. 2011;12:535–545.
   PubMed Web of Science ®Google Scholar
• Meda F, Folci M, Baccarelli A, et al. The epigenetics of autoimmunity. Cell Mol Immunol. 2011;8:226–236.
   PubMed Web of Science ®Google Scholar
• Mann DA. Epigenetics in liver disease. Hepatology. 2014;60:1418–1425.
   PubMed Web of Science ®Google Scholar
• Canas CA, Canas F, Bonilla-Abadia F, et al. Epigenetics changes associated to environmental triggers in autoimmunity. Autoimmunity. 2016;49:1–11.
   PubMed Web of Science ®Google Scholar
• Czaja AJ. Global disparities and their implications in the occurrence and outcome of autoimmune hepatitis. Dig Dis Sci. 2017;62:2277–2292.
   PubMed Web of Science ®Google Scholar
• Czaja AJ. Epigenetic changes and their implications in autoimmune hepatitis. Eur J Clin Invest. 2018;48:e12899.
   Web of Science ®Google Scholar
• Christen U, von Herrath MG. Induction, acceleration or prevention of autoimmunity by molecular mimicry. Mol Immunol. 2004;40:1113–1120.
   PubMed Web of Science ®Google Scholar
• Ehser J, Holdener M, Christen S, et al. Molecular mimicry rather than identity breaks T-cell tolerance in the CYP2D6 mouse model for human autoimmune hepatitis. J Autoimmun. 2013;42:39–49.
   PubMed Web of Science ®Google Scholar
• Hintermann E, Holdener M, Bayer M, et al. Epitope spreading of the anti-CYP2D6 antibody response in patients with autoimmune hepatitis and in the CYP2D6 mouse model. J Autoimmun. 2011;37:242–253.
   PubMed Web of Science ®Google Scholar
• Manns MP, Czaja AJ, Gorham JD, et al. Diagnosis and management of autoimmune hepatitis. Hepatology. 2010;51:2193–2213.
   PubMed Web of Science ®Google Scholar
• Gleeson D, Heneghan MA. British Society of Gastroenterology (BSG) guidelines for management of autoimmune hepatitis. Gut. 2011;60:1611–1629.
   PubMed Web of Science ®Google Scholar
• EASL Clinical Practice Guidelines: autoimmune hepatitis. J Hepatol. 2015;63:971–1004.
   PubMed Web of Science ®Google Scholar
• Czaja AJ. Promising pharmacological, molecular and cellular treatments of autoimmune hepatitis. Curr Pharm Des. 2011;17:3120–3140.
   PubMed Web of Science ®Google Scholar
• Czaja AJ. Nonstandard drugs and feasible new interventions for autoimmune hepatitis. Part—II. Inflamm Allergy Drug Targets. 2012;11:351–363.
   PubMedGoogle Scholar
• Czaja AJ. Current and prospective pharmacotherapy for autoimmune hepatitis. Expert Opin Pharmacother. 2014;15:1715–1736.
   PubMed Web of Science ®Google Scholar
• Czaja AJ. Review article: next-generation transformative advances in the pathogenesis and management of autoimmune hepatitis. Aliment Pharmacol Ther. 2017;46:920–937.
   PubMed Web of Science ®Google Scholar
• Czaja AJ. Evolving paradigm of treatment for autoimmune hepatitis. Expert Rev Clin Immunol. 2017;13:781–798.
   PubMed Web of Science ®Google Scholar
• Weiler-Normann C, Schramm C, Quaas A, et al. Infliximab as a rescue treatment in difficult-to-treat autoimmune hepatitis. J Hepatol. 2013;58:529–534.
   PubMed Web of Science ®Google Scholar
• Santos ES, Arosemena LR, Raez LE, et al. Successful treatment of autoimmune hepatitis and idiopathic thrombocytopenic purpura with the monoclonal antibody, rituximab: case report and review of literature. Liver Int. 2006;26:625–629.
   PubMed Web of Science ®Google Scholar
• Evans JT, Shepard MM, Oates JC, et al. Rituximab-responsive cryoglobulinemic glomerulonephritis in a patient with autoimmune hepatitis. J Clin Gastroenterol. 2008;42:862–863.
   PubMed Web of Science ®Google Scholar
• Barth E, Clawson J. A case of autoimmune hepatitis treated with rituximab. Case Rep Gastroenterol. 2010;4:502–509.
   PubMedGoogle Scholar
• Carey EJ, Somaratne K, Rakela J. Successful rituximab therapy in refractory autoimmune hepatitis and Evans syndrome. Rev Méd Chile. 2011;139:1484–1487.
   PubMed Web of Science ®Google Scholar
• Burak KW, Swain MG, Santodomino-Garzon T, et al. Rituximab for the treatment of patients with autoimmune hepatitis who are refractory or intolerant to standard therapy. Can J Gastroenterol. 2013;27:273–280.
   PubMed Web of Science ®Google Scholar
• Sutherland AP, Ng LG, Fletcher CA, et al. BAFF augments certain Th1-associated inflammatory responses. J Immunol. 2005;174:5537–5544.
   PubMed Web of Science ®Google Scholar
• Migita K, Abiru S, Maeda Y, et al. Elevated serum BAFF levels in patients with autoimmune hepatitis. Hum Immunol. 2007;68:586–591.
   PubMed Web of Science ®Google Scholar
• Nishikawa H, Enomoto H, Iwata Y, et al. B-cell activating factor belonging to the tumor necrosis factor family and interferon-γ-inducible protein-10 in autoimmune hepatitis. Medicine. 2016;95:e3194.
   PubMed Web of Science ®Google Scholar
• Hokland P, Hokland M, Cotter F. The Nobel Prize for Medicine awarded for cancer therapy by inhibition of negative immune regulation. Br J Haematol. 2018;183:698–700.
   PubMed Web of Science ®Google Scholar
• Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 2018;8:1069–1086.
   PubMed Web of Science ®Google Scholar
• Conway JR, Kofman E, Mo SS, et al. Genomics of response to immune checkpoint therapies for cancer: implications for precision medicine. Genome Med. 2018;10:93.
   PubMed Web of Science ®Google Scholar
• Karachaliou N, Rosell R. Science and biology drives the immune system to cure lung cancer patients: a revolution but not without challenges. Ther Adv Med Oncol. 2018;10:1758835918763723.
   Web of Science ®Google Scholar
• Karachaliou N, Fernandez-Bruno M, Bracht JWP, et al. Challenges and unanswered questions for the next decade of immune-oncology research in NSCLC. Transl Lung Cancer Res. 2018;7:691–702.
   PubMed Web of Science ®Google Scholar
• Chokr N, Patel R, Wattamwar K, et al. The rising era of immune checkpoint inhibitors in myelodysplastic syndromes. Adv Hematol. 2018;2018:1.
   Google Scholar
• He XS, Gershwin ME, Ansari AA. Checkpoint-based immunotherapy for autoimmune diseases – opportunities and challenges. J Autoimmun. 2017;79:1–3.
   PubMed Web of Science ®Google Scholar
• Ishida Y, Agata Y, Shibahara K, et al. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. Embo J. 1992;11:3887–3895.
   PubMed Web of Science ®Google Scholar
• Agata Y, Kawasaki A, Nishimura H, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol. 1996;8:765–772.
   PubMed Web of Science ®Google Scholar
• Nishimura H, Honjo T. PD-1: an inhibitory immunoreceptor involved in peripheral tolerance. Trends Immunol. 2001;22:265–268.
   PubMed Web of Science ®Google Scholar
• Fife BT, Pauken KE, Eagar TN, et al. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol. 2009;10:1185–1192.
   PubMed Web of Science ®Google Scholar
• Thibult ML, Mamessier E, Gertner-Dardenne J, et al. PD-1 is a novel regulator of human B-cell activation. Int Immunol. 2013;25:129–137.
   PubMed Web of Science ®Google Scholar
• Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192:1027–1034.
   PubMed Web of Science ®Google Scholar
• Ishida M, Iwai Y, Tanaka Y, et al. Differential expression of PD-L1 and PD-L2, ligands for an inhibitory receptor PD-1, in the cells of lymphohematopoietic tissues. Immunol Lett. 2002;84:57–62.
   PubMed Web of Science ®Google Scholar
• Yamazaki T, Akiba H, Iwai H, et al. Expression of programmed death 1 ligands by murine T cells and APC. J Immunol. 2002;169:5538–5545.
   PubMed Web of Science ®Google Scholar
• Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med. 1995;182:459–465.
   PubMed Web of Science ®Google Scholar
• Brunner MC, Chambers CA, Chan FK, et al. CTLA-4-mediated inhibition of early events of T cell proliferation. J Immunol. 1999;162:5813–5820.
   PubMed Web of Science ®Google Scholar
• Peggs KS, Quezada SA, Chambers CA, et al. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med. 2009;206:1717–1725.
   PubMed Web of Science ®Google Scholar
• Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012;24:207–212.
   PubMed Web of Science ®Google Scholar
• Quezada SA, Peggs KS. Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host immune response against cancer. Br J Cancer. 2013;108:1560–1565.
   PubMed Web of Science ®Google Scholar
• Riaz N, Morris L, Havel JJ, et al. The role of neoantigens in response to immune checkpoint blockade. Intimm. 2016;28:411–419.
   PubMed Web of Science ®Google Scholar
• van der Vlist M, Kuball J, Radstake TR, et al. Immune checkpoints and rheumatic diseases: what can cancer immunotherapy teach us? Nat Rev Rheumatol. 2016;12:593–604.
   PubMed Web of Science ®Google Scholar
• Czaja AJ. Under-evaluated or unassessed pathogenic pathways in autoimmune hepatitis and implications for future management. Dig Dis Sci. 2018;63:1706–1725.
   PubMed Web of Science ®Google Scholar
• Young A, Quandt Z, Bluestone JA. The balancing act between cancer immunity and autoimmunity in response to immunotherapy. Cancer Immunol Res. 2018;6:1445–1452.
   PubMed Web of Science ®Google Scholar
• Myers G. Immune-related adverse events of immune checkpoint inhibitors: a brief review. Curr Oncol. 2018;25:342–347.
   PubMed Web of Science ®Google Scholar
• Waterhouse P, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995;270:985–988.
   PubMed Web of Science ®Google Scholar
• Tivol EA, Borriello F, Schweitzer AN, et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995;3:541–547.
   PubMed Web of Science ®Google Scholar
• Wing K, Onishi Y, Prieto-Martin P, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322:271–275.
   PubMed Web of Science ®Google Scholar
• Tocut M, Brenner R, Zandman-Goddard G. Autoimmune phenomena and disease in cancer patients treated with immune checkpoint inhibitors. Autoimmun Rev. 2018;17:610–616.
   PubMed Web of Science ®Google Scholar
• King GT, Sharma P, Davis SL, et al. Immune and autoimmune-related adverse events associated with immune checkpoint inhibitors in cancer therapy. Drugs Today. 2018;54:103–122.
   PubMed Web of Science ®Google Scholar
• Akturk HK, Alkanani A, Zhao Z, et al. PD-1 inhibitor immune-related adverse events in patients with preexisting endocrine autoimmunity. J Clin Endocrinol Metab. 2018;103:3589–3592.
   PubMed Web of Science ®Google Scholar
• Parakh S, Cebon J, Klein O. Delayed autoimmune toxicity occurring several months after cessation of anti-PD-1 therapy. Oncologist. 2018;23:849–851.
   PubMed Web of Science ®Google Scholar
• Kleiner DE, Berman D. Pathologic changes in ipilimumab-related hepatitis in patients with metastatic melanoma. Dig Dis Sci. 2012;57:2233–2240.
   PubMed Web of Science ®Google Scholar
• Kim KW, Ramaiya NH, Krajewski KM, et al. Ipilimumab associated hepatitis: imaging and clinicopathologic findings. Invest New Drugs. 2013;31:1071–1077.
   PubMed Web of Science ®Google Scholar
• Johncilla M, Misdraji J, Pratt DS, et al. Ipilimumab-associated hepatitis: clinicopathologic characterization in a series of 11 cases. Am J Surg Pathol. 2015;39:1075–1084.
   PubMed Web of Science ®Google Scholar
• Everett J, Srivastava A, Misdraji J. Fibrin ring granulomas in checkpoint inhibitor-induced hepatitis. Am J Surg Pathol. 2017;41:134–137.
   PubMed Web of Science ®Google Scholar
• Reddy HG, Schneider BJ, Tai AW. Immune checkpoint inhibitor-associated colits and hepatitis. Clin Transl Gastroenterol. 2018;9:180.
   PubMed Web of Science ®Google Scholar
• Reynolds K, Thomas M, Dougan M. Diagnosis and management of hepatitis in patients on checkpoint blockade. Oncologist. 2018;23:991–997.
   PubMed Web of Science ®Google Scholar
• Suzman DL, Pelosof L, Rosenberg A, et al. Hepatotoxicity of immune checkpoint inhibitors: an evolving picture of risk associated with a vital class of immunotherapy agents. Liver Int. 2018;38:976–987.
   PubMed Web of Science ®Google Scholar
• Zen Y, Yeh MM. Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury. Mod Pathol. 2018;31:965–973.
   PubMed Web of Science ®Google Scholar
• De Martin E, Michot JM, Papouin B, et al. Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors. J Hepatol. 2018;68:1181–1190.
   PubMed Web of Science ®Google Scholar
• Nishida N, Kudo M. Liver damage related to immune checkpoint inhibitors. Hepatol Int. 2019;13:248.
   PubMed Web of Science ®Google Scholar
• Jennings JJ, Mandaliya R, Nakshabandi A, et al. Hepatotoxicity induced by immune checkpoint inhibitors: a comprehensive review including current and alternative management strategies. Expert Opin Drug Metab Toxicol. 2019;15:231–244.
   PubMed Web of Science ®Google Scholar
• Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer–preclinical background: CTLA-4 and PD-1 blockade. Semin Oncol. 2010;37:430–439.
   PubMed Web of Science ®Google Scholar
• Darvin P, Toor SM, Sasidharan Nair V, et al. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med. 2018;50:165.
   PubMed Web of Science ®Google Scholar
• Linsley PS, Greene JL, Tan P, et al. Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes. J Exp Med. 1992;176:1595–1604.
   PubMed Web of Science ®Google Scholar
• Walunas TL, Lenschow DJ, Bakker CY, et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity. 1994;1:405–413.
   PubMed Web of Science ®Google Scholar
• Bluestone JA. Is CTLA-4 a master switch for peripheral T cell tolerance? J Immunol. 1997;158:1989–1993.
   PubMed Web of Science ®Google Scholar
• Thompson CB, Allison JP. The emerging role of CTLA-4 as an immune attenuator. Immunity. 1997;7:445–450.
   PubMed Web of Science ®Google Scholar
• Rudd CE, Taylor A, Schneider H. CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev. 2009;229:12–26.
   PubMed Web of Science ®Google Scholar
• Linsley PS, Bradshaw J, Greene J, et al. Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement. Immunity. 1996;4:535–543.
   PubMed Web of Science ®Google Scholar
• Alegre ML, Noel PJ, Eisfelder BJ, et al. Regulation of surface and intracellular expression of CTLA4 on mouse T cells. J Immunol. 1996;157:4762–4770.
   PubMed Web of Science ®Google Scholar
• Freeman GJ, Lombard DB, Gimmi CD, et al. CTLA-4 and CD28 mRNA are coexpressed in most T cells after activation. Expression of CTLA-4 and CD28 mRNA does not correlate with the pattern of lymphokine production. J Immunol. 1992;149:3795–3801.
   PubMed Web of Science ®Google Scholar
• Metzler B, Burkhart C, Wraith DC. Phenotypic analysis of CTLA-4 and CD28 expression during transient peptide-induced T cell activation in vivo. Int Immunol. 1999;11:667–675.
   PubMed Web of Science ®Google Scholar
• Prasad KV, Cai YC, Raab M, et al. T-cell antigen CD28 interacts with the lipid kinase phosphatidylinositol 3-kinase by a cytoplasmic Tyr(P)-Met-Xaa-Met motif. Proc Natl Acad Sci USA. 1994;91:2834–2838.
   PubMed Web of Science ®Google Scholar
• Schneider H, Cai YC, Prasad KV, et al. T cell antigen CD28 binds to the GRB-2/SOS complex, regulators of p21ras. Eur J Immunol. 1995;25:1044–1050.
   PubMed Web of Science ®Google Scholar
• Greenfield EA, Nguyen KA, Kuchroo VK. CD28/B7 costimulation: a review. Crit Rev Immunol. 1998;18:389–418.
   PubMed Web of Science ®Google Scholar
• Linsley PS, Brady W, Urnes M, et al. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med. 1991;174:561–569.
   PubMed Web of Science ®Google Scholar
• Walunas TL, Bakker CY, Bluestone JA. CTLA-4 ligation blocks CD28-dependent T cell activation. J Exp Med. 1996;183:2541–2550.
   PubMed Web of Science ®Google Scholar
• Carreno BM, Bennett F, Chau TA, et al. CTLA-4 (CD152) can inhibit T cell activation by two different mechanisms depending on its level of cell surface expression. J Immunol. 2000;165:1352–1356.
   PubMed Web of Science ®Google Scholar
• Masteller EL, Chuang E, Mullen AC, et al. Structural analysis of CTLA-4 function in vivo. J Immunol. 2000;164:5319–5327.
   PubMed Web of Science ®Google Scholar
• Riley JL, June CH. The CD28 family: a T-cell rheostat for therapeutic control of T-cell activation. Blood. 2005;105:13–21.
   PubMed Web of Science ®Google Scholar
• Schildberg FA, Klein SR, Freeman GJ, et al. Coinhibitory pathways in the B7-CD28 ligand-receptor family. Immunity. 2016;44:955–972.
   PubMed Web of Science ®Google Scholar
• Chambers CA, Kuhns MS, Allison JP. Cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates primary and secondary peptide-specific CD4(+) T cell responses. Proc Natl Acad Sci USA. 1999;96:8603–8608.
   PubMed Web of Science ®Google Scholar
• McCoy KD, Le Gros G. The role of CTLA-4 in the regulation of T cell immune responses. Immunol Cell Biol. 1999;77:1–10.
   PubMed Web of Science ®Google Scholar
• Chikuma S, Abbas AK, Bluestone JA. B7-independent inhibition of T cells by CTLA-4. J Immunol. 2005;175:177–181.
   PubMed Web of Science ®Google Scholar
• Wang CJ, Kenefeck R, Wardzinski L, et al. Cutting edge: cell-extrinsic immune regulation by CTLA-4 expressed on conventional T cells. J Immunol. 2012;189:1118–1122.
   PubMed Web of Science ®Google Scholar
• Walker L. EFIS lecture: understanding the CTLA-4 checkpoint in the maintenance of immune homeostasis. Immunol Lett. 2017;184:43–50.
   PubMed Web of Science ®Google Scholar
• Brunner-Weinzierl MC, Rudd CE. CTLA-4 and PD-1 control of T-cell motility and migration: implications for tumor immunotherapy. Front Immunol. 2018;9:2737.
   PubMed Web of Science ®Google Scholar
• Elrefaei M, Burke CM, Baker CA, et al. TGF-beta and IL-10 production by HIV-specific CD8+ T cells is regulated by CTLA-4 signaling on CD4+ T cells. PLoS One. 2009;4:e8194.
   PubMed Web of Science ®Google Scholar
• Zheng SG, Wang JH, Stohl W, et al. TGF-beta requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4 + CD25+ regulatory cells. J Immunol. 2006;176:3321–3329.
   PubMed Web of Science ®Google Scholar
• Takahashi T, Tagami T, Yamazaki S, et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med. 2000;192:303–310.
   PubMed Web of Science ®Google Scholar
• Read S, Malmstrom V, Powrie F. 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. 2000;192:295–302.
   PubMed Web of Science ®Google Scholar
• Tang Q, Boden EK, Henriksen KJ, et al. Distinct roles of CTLA-4 and TGF-beta in CD4 + CD25+ regulatory T cell function. Eur J Immunol. 2004;34:2996–3005.
   PubMed Web of Science ®Google Scholar
• Kolar P, Knieke K, Hegel JK, et al. CTLA-4 (CD152) controls homeostasis and suppressive capacity of regulatory T cells in mice. Arthritis Rheum. 2009;60:123–132.
   PubMed Web of Science ®Google Scholar
• Yamaguchi T, Kishi A, Osaki M, et al. Construction of self-recognizing regulatory T cells from conventional T cells by controlling CTLA-4 and IL-2 expression. Proc Natl Acad Sci U S A. 2013;110:E2116–E2125.
   PubMed Web of Science ®Google Scholar
• Rudd CE. The reverse stop-signal model for CTLA4 function. Nat Rev Immunol. 2008;8:153–160.
   PubMed Web of Science ®Google Scholar
• Knieke K, Hoff H, Maszyna F, et al. CD152 (CTLA-4) determines CD4 T cell migration in vitro and in vivo. PLoS One. 2009;4:e5702.
   PubMed Web of Science ®Google Scholar
• Jain N, Nguyen H, Chambers C, et al. Dual function of CTLA-4 in regulatory T cells and conventional T cells to prevent multiorgan autoimmunity. Proc Natl Acad Sci USA. 2010;107:1524–1528.
   PubMed Web of Science ®Google Scholar
• Cinek T, Sadra A, Imboden JB. Cutting edge: tyrosine-independent transmission of inhibitory signals by CTLA-4. J Immunol. 2000;164:5–8.
   PubMed Web of Science ®Google Scholar
• Egen JG, Allison JP. Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity. 2002;16:23–35.
   PubMed Web of Science ®Google Scholar
• Pentcheva-Hoang T, Egen JG, Wojnoonski K, et al. B7-1 and B7-2 selectively recruit CTLA-4 and CD28 to the immunological synapse. Immunity. 2004;21:401–413.
   PubMed Web of Science ®Google Scholar
• Qureshi OS, Zheng Y, Nakamura K, et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science. 2011;332:600–603.
   PubMed Web of Science ®Google Scholar
• Mellor AL, Keskin DB, Johnson T, et al. Cells expressing indoleamine 2,3-dioxygenase inhibit T cell responses. J Immunol. 2002;168:3771–3776.
   PubMed Web of Science ®Google Scholar
• Fallarino F, Grohmann U, Vacca C, et al. T cell apoptosis by tryptophan catabolism. Cell Death Differ. 2002;9:1069–1077.
   PubMed Web of Science ®Google Scholar
• Hoff H, Kolar P, Ambach A, et al. CTLA-4 (CD152) inhibits T cell function by activating the ubiquitin ligase Itch. Mol Immunol. 2010;47:1875–1881.
   PubMed Web of Science ®Google Scholar
• Lingel H, Wissing J, Arra A, et al. CTLA-4-mediated posttranslational modifications direct cytotoxic T-lymphocyte differentiation. Cell Death Differ. 2017;24:1739–1749.
   PubMed Web of Science ®Google Scholar
• Oaks MK, Hallett KM. Cutting edge: a soluble form of CTLA-4 in patients with autoimmune thyroid disease. J Immunol. 2000;164:5015–5018.
   PubMed Web of Science ®Google Scholar
• Oaks MK, Hallett KM, Penwell RT, et al. A native soluble form of CTLA-4. Cell Immunol. 2000;201:144–153.
   PubMed Web of Science ®Google Scholar
• Saverino D, Brizzolara R, Simone R, et al. Soluble CTLA-4 in autoimmune thyroid diseases: relationship with clinical status and possible role in the immune response dysregulation. Clin Immunol. 2007;123:190–198.
   PubMed Web of Science ®Google Scholar
• Saverino D, Simone R, Bagnasco M, et al. The soluble CTLA-4 receptor and its role in autoimmune diseases: an update. Auto Immun Highlights. 2010;1:73–81.
   PubMedGoogle Scholar
• Dahal LN, Basu N, Youssef H, et al. Immunoregulatory soluble CTLA-4 modifies effector T-cell responses in systemic lupus erythematosus. Arthritis Res Ther. 2016;18:180.
   PubMed Web of Science ®Google Scholar
• Liu Q, Hu P, Deng G, et al. Soluble cytotoxic T-lymphocyte antigen 4: a favorable predictor in malignant tumors after therapy. Ott. 2017;10:2147–2154.
   Google Scholar
• Daroszewski J, Pawlak E, Karabon L, et al. Soluble CTLA-4 receptor an immunological marker of Graves' disease and severity of ophthalmopathy is associated with CTLA-4 Jo31 and CT60 gene polymorphisms. Eur J Endocrinol. 2009;161:787–793.
   PubMed Web of Science ®Google Scholar
• Liu MF, Wang CR, Chen PC, et al. Increased expression of soluble cytotoxic T-lymphocyte-associated antigen-4 molecule in patients with systemic lupus erythematosus. Scand J Immunol. 2003;57:568–572.
   PubMed Web of Science ®Google Scholar
• Wong CK, Lit LC, Tam LS, et al. Aberrant production of soluble costimulatory molecules CTLA-4, CD28, CD80 and CD86 in patients with systemic lupus erythematosus. Rheumatology. 2005;44:989–994.
   PubMed Web of Science ®Google Scholar
• Sato S, Fujimoto M, Hasegawa M, et al. Serum soluble CTLA-4 levels are increased in diffuse cutaneous systemic sclerosis. Rheumatology. 2004;43:1261–1266.
   PubMed Web of Science ®Google Scholar
• Umemura T, Ota M, Yoshizawa K, et al. Association of cytotoxic T-lymphocyte antigen 4 gene polymorphisms with type 1 autoimmune hepatitis in Japanese. Hepatol Res. 2008;38:689–695.
   PubMed Web of Science ®Google Scholar
• Simone R, Brizzolara R, Chiappori A, et al. A functional soluble form of CTLA-4 is present in the serum of celiac patients and correlates with mucosal injury. Int Immunol. 2009;21:1037–1045.
   PubMed Web of Science ®Google Scholar
• Wang XB, Kakoulidou M, Giscombe R, et al. Abnormal expression of CTLA-4 by T cells from patients with myasthenia gravis: effect of an AT-rich gene sequence. J Neuroimmunol. 2002;130:224–232.
   PubMed Web of Science ®Google Scholar
• Cetintepe SP, Senturk T, Sargin G, et al. Serum sCTLA-4 levels and clinical manifestations in ankylosing spondylitis patients. Eur J Rheumatol. 2018;5:115–117.
   PubMed Web of Science ®Google Scholar
• Pistillo MP, Fontana V, Morabito A, et al. Soluble CTLA-4 as a favorable predictive biomarker in metastatic melanoma patients treated with ipilimumab: an Italian melanoma intergroup study. Cancer Immunol Immunother. 2019;68:97–107.
   PubMed Web of Science ®Google Scholar
• Brown JA, Dorfman DM, Ma FR, et al. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol. 2003;170:1257–1266.
   PubMed Web of Science ®Google Scholar
• Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.
   PubMed Web of Science ®Google Scholar
• Boussiotis VA. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl J Med. 2016;375:1767–1778.
   PubMed Web of Science ®Google Scholar
• Bardhan K, Anagnostou T, Boussiotis VA. The PD1:PD-L1/2 pathway from discovery to clinical implementation. Front Immunol. 2016;7:550.
   PubMed Web of Science ®Google Scholar
• Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol. 2002;2:116–126.
   PubMed Web of Science ®Google Scholar
• Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13:227–242.
   PubMed Web of Science ®Google Scholar
• Zamani MR, Aslani S, Salmaninejad A, et al. PD-1/PD-L and autoimmunity: a growing relationship. Cell Immunol. 2016;310:27–41.
   PubMed Web of Science ®Google Scholar
• Iwai Y, Okazaki T, Nishimura H, et al. Microanatomical localization of PD-1 in human tonsils. Immunol Lett. 2002;83:215–220.
   PubMed Web of Science ®Google Scholar
• Mataki N, Kikuchi K, Kawai T, et al. Expression of PD-1, PD-L1, and PD-L2 in the liver in autoimmune liver diseases. Am J Gastroenterol. 2007;102:302–312.
   PubMed Web of Science ®Google Scholar
• Liu Y, Cheng Y, Xu Y, et al. Increased expression of programmed cell death protein 1 on NK cells inhibits NK-cell-mediated anti-tumor function and indicates poor prognosis in digestive cancers. Oncogene. 2017;36:6143–6153.
   PubMed Web of Science ®Google Scholar
• Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2:261–268.
   PubMed Web of Science ®Google Scholar
• Dong H, Zhu G, Tamada K, et al. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5:1365–1369.
   PubMed Web of Science ®Google Scholar
• Tseng SY, Otsuji M, Gorski K, et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med. 2001;193:839–846.
   PubMed Web of Science ®Google Scholar
• Loke P, Allison JP. PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells. Proc Natl Acad Sci USA. 2003;100:5336–5341.
   PubMed Web of Science ®Google Scholar
• Okazaki T, Maeda A, Nishimura H, et al. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A. 2001;98:13866–13871.
   PubMed Web of Science ®Google Scholar
• Sheppard KA, Fitz LJ, Lee JM, et al. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett. 2004;574:37–41.
   PubMed Web of Science ®Google Scholar
• Daeron M, Jaeger S, Du Pasquier L, et al. Immunoreceptor tyrosine-based inhibition motifs: a quest in the past and future. Immunol Rev. 2008;224:11–43.
   PubMed Web of Science ®Google Scholar
• Neel BG, Gu H, Pao L. The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem Sci. 2003;28:284–293.
   PubMed Web of Science ®Google Scholar
• Lorenz U. SHP-1 and SHP-2 in T cells: two phosphatases functioning at many levels. Immunol Rev. 2009;228:342–359.
   PubMed Web of Science ®Google Scholar
• Nishimura H, Honjo T, Minato N. Facilitation of beta selection and modification of positive selection in the thymus of PD-1-deficient mice. J Exp Med. 2000;191:891–898.
   PubMed Web of Science ®Google Scholar
• Jiang TT, Martinov T, Xin L, et al. Programmed death-1 culls peripheral accumulation of high-affinity autoreactive CD4 T cells to protect against autoimmunity. Cell Rep. 2016;17:1783–1794.
   PubMed Web of Science ®Google Scholar
• Hsieh CS, Zheng Y, Liang Y, et al. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat Immunol. 2006;7:401–410.
   PubMed Web of Science ®Google Scholar
• Bautista JL, Lio CW, Lathrop SK, et al. Intraclonal competition limits the fate determination of regulatory T cells in the thymus. Nat Immunol. 2009;10:610–617.
   PubMed Web of Science ®Google Scholar
• Moon JJ, Dash P, Oguin TH, et al. Quantitative impact of thymic selection on Foxp3+ and Foxp3- subsets of self-peptide/MHC class II-specific CD4+ T cells. Proc Natl Acad Sci USA. 2011;108:14602–14607.
   PubMed Web of Science ®Google Scholar
• Legoux FP, Lim JB, Cauley AW, et al. CD4+ T cell tolerance to tissue-restricted self antigens is mediated by antigen-specific regulatory T cells rather than deletion. Immunity. 2015;43:896–908.
   PubMed Web of Science ®Google Scholar
• Ellestad KK, Thangavelu G, Haile Y, et al. Prior to peripheral tolerance, newly generated CD4 T cells maintain dangerous autoimmune potential: fas- and perforin-independent autoimmunity controlled by Programmed Death-1. Front Immunol. 2018;9:12.
   PubMed Web of Science ®Google Scholar
• Thangavelu G, Parkman JC, Ewen CL, et al. Programmed death-1 is required for systemic self-tolerance in newly generated T cells during the establishment of immune homeostasis. J Autoimmun. 2011;36:301–312.
   PubMed Web of Science ®Google Scholar
• Yao S, Wang S, Zhu Y, et al. PD-1 on dendritic cells impedes innate immunity against bacterial infection. Blood. 2009;113:5811–5818.
   PubMed Web of Science ®Google Scholar
• Lim TS, Chew V, Sieow JL, et al. PD-1 expression on dendritic cells suppresses CD8(+) T cell function and antitumor immunity. Oncoimmunology. 2016;5:e1085146.
   PubMed Web of Science ®Google Scholar
• Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010;236:219–242.
   PubMed Web of Science ®Google Scholar
• Francisco LM, Salinas VH, Brown KE, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009;206:3015–3029.
   PubMed Web of Science ®Google Scholar
• Wang W, Lau R, Yu D, et al. PD1 blockade reverses the suppression of melanoma antigen-specific CTL by CD4+ CD25(Hi) regulatory T cells. Int Immunol. 2009;21:1065–1077.
   PubMed Web of Science ®Google Scholar
• Park SJ, Namkoong H, Doh J, et al. Negative role of inducible PD-1 on survival of activated dendritic cells. J Leukoc Biol. 2014;95:621–629.
   PubMed Web of Science ®Google Scholar
• Krempski J, Karyampudi L, Behrens MD, et al. Tumor-infiltrating programmed death receptor-1+ dendritic cells mediate immune suppression in ovarian cancer. JI. 2011;186:6905–6913.
   Google Scholar
• Wang L, Pino-Lagos K, de Vries VC, et al. Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3 + CD4+ regulatory T cells. Proc Natl Acad Sci USA. 2008;105:9331–9336.
   PubMed Web of Science ®Google Scholar
• Gotot J, Gottschalk C, Leopold S, et al. Regulatory T cells use programmed death 1 ligands to directly suppress autoreactive B cells in vivo. Proc Natl Acad Sci USA. 2012;109:10468–10473.
   PubMed Web of Science ®Google Scholar
• Mazanet MM, Hughes CC. B7-H1 is expressed by human endothelial cells and suppresses T cell cytokine synthesis. J Immunol. 2002;169:3581–3588.
   PubMed Web of Science ®Google Scholar
• Gianchecchi E, Fierabracci A. Inhibitory receptors and pathways of lymphocytes: the role of PD-1 in Treg development and their involvement in autoimmunity onset and cancer progression. Front Immunol. 2018;9:2374.
   PubMed Web of Science ®Google Scholar
• Kido M, Watanabe N, Okazaki T, et al. Fatal autoimmune hepatitis induced by concurrent loss of naturally arising regulatory T cells and PD-1-mediated signaling. Gastroenterology. 2008;135:1333–1343.
   PubMed Web of Science ®Google Scholar
• Nielsen C, Ohm-Laursen L, Barington T, et al. Alternative splice variants of the human PD-1 gene. Cell Immunol. 2005;235:109–116.
   PubMed Web of Science ®Google Scholar
• Pen JJ, Keersmaecker BD, Heirman C, et al. Interference with PD-L1/PD-1 co-stimulation during antigen presentation enhances the multifunctionality of antigen-specific T cells. Gene Ther. 2014;21:262–271.
   PubMed Web of Science ®Google Scholar
• Song MY, Park SH, Nam HJ, et al. Enhancement of vaccine-induced primary and memory CD8(+) T-cell responses by soluble PD-1. J Immunother. 2011;34:297–306.
   PubMed Web of Science ®Google Scholar
• Wan B, Nie H, Liu A, et al. Aberrant regulation of synovial T cell activation by soluble costimulatory molecules in rheumatoid arthritis. J Immunol. 2006;177:8844–8850.
   PubMed Web of Science ®Google Scholar
• Onlamoon N, Rogers K, Mayne AE, et al. Soluble PD-1 rescues the proliferative response of simian immunodeficiency virus-specific CD4 and CD8 T cells during chronic infection. Immunology. 2008;124:277–293.
   PubMed Web of Science ®Google Scholar
• Zhu X, Lang J. Soluble PD-1 and PD-L1: predictive and prognostic significance in cancer. Oncotarget. 2017;8:97671–97682.
   PubMedGoogle Scholar
• Guo Y, Walsh AM, Canavan M, et al. Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression. PLoS One. 2018;13:e0192704.
   PubMed Web of Science ®Google Scholar
• Carter L, Fouser LA, Jussif J, et al. PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2. Eur J Immunol. 2002;32:634–643.
   PubMed Web of Science ®Google Scholar
• Kythreotou A, Siddique A, Mauri FA, et al. PD-L1. J Clin Pathol. 2018;71:189–194.
   PubMed Web of Science ®Google Scholar
• Jain P, Jain C, Velcheti V. Role of immune-checkpoint inhibitors in lung cancer. Ther Adv Respir Dis. 2018;12:1753465817750075.
   Web of Science ®Google Scholar
• Karachaliou N, Gonzalez-Cao M, Crespo G, et al. Interferon gamma, an important marker of response to immune checkpoint blockade in non-small cell lung cancer and melanoma patients. Ther Adv Med Oncol. 2018;10:175883401774974.
   Web of Science ®Google Scholar
• Butte MJ, Keir ME, Phamduy TB, et al. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007;27:111–122.
   PubMed Web of Science ®Google Scholar
• Keir ME, Liang SC, Guleria I, et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med. 2006;203:883–895.
   PubMed Web of Science ®Google Scholar
• Sage PT, Schildberg FA, Sobel RA, et al. Dendritic cell PD-L1 limits autoimmunity and follicular T cell differentiation and function. J Immunol. 2018;200:2592–2602.
   PubMed Web of Science ®Google Scholar
• Juchem KW, Sacirbegovic F, Zhang C, et al. PD-L1 prevents the development of autoimmune heart disease in Graft-versus-Host disease. J Immunol. 2018;200:834–846.
   PubMed Web of Science ®Google Scholar
• Kuipers H, Muskens F, Willart M, et al. Contribution of the PD-1 ligands/PD-1 signaling pathway to dendritic cell-mediated CD4+ T cell activation. Eur J Immunol. 2006;36:2472–2482.
   PubMed Web of Science ®Google Scholar
• Talay O, Shen CH, Chen L, et al. B7-H1 (PD-L1) on T cells is required for T-cell-mediated conditioning of dendritic cell maturation. Proc Natl Acad Sci USA. 2009;106:2741–2746.
   PubMed Web of Science ®Google Scholar
• Tamura H, Dong H, Zhu G, et al. B7-H1 costimulation preferentially enhances CD28-independent T-helper cell function. Blood. 2001;97:1809–1816.
   PubMed Web of Science ®Google Scholar
• Shin T, Kennedy G, Gorski K, et al. Cooperative B7-1/2 (CD80/CD86) and B7-DC costimulation of CD4+ T cells independent of the PD-1 receptor. J Exp Med. 2003;198:31–38.
   PubMed Web of Science ®Google Scholar
• Garcia-Bates TM, Palma ML, Shen C, et al. Contrasting roles of the PD-1 signaling pathway in dendritic cell-mediated induction and regulation of HIV-1-specific effector T cell functions. J Virol. 2018;93:e02035–e02018.
   Web of Science ®Google Scholar
• Frigola X, Inman BA, Krco CJ, et al. Soluble B7-H1: differences in production between dendritic cells and T cells. Immunol Lett. 2012;142:78–82.
   PubMed Web of Science ®Google Scholar
• Chen Y, Wang Q, Shi B, et al. Development of a sandwich ELISA for evaluating soluble PD-L1 (CD274) in human sera of different ages as well as supernatants of PD-L1+ cell lines. Cytokine. 2011;56:231–238.
   PubMed Web of Science ®Google Scholar
• Li Y, Xiao Y, Su M, et al. Role of soluble programmed death-1 (sPD-1) and sPD-ligand 1 in patients with cystic echinococcosis. Exp Ther Med. 2016;11:251–256.
   PubMed Web of Science ®Google Scholar
• Wei W, Xu B, Wang Y, et al. Prognostic significance of circulating soluble programmed death ligand-1 in patients with solid tumors: a meta-analysis. Medicine. 2018;97:e9617.
   PubMed Web of Science ®Google Scholar
• Aarslev K, Dige A, Greisen SR, et al. Soluble programmed death-1 levels are associated with disease activity and treatment response in patients with autoimmune hepatitis. Scand J Gastroenterol. 2017;52:93–99.
   PubMed Web of Science ®Google Scholar
• Nishimura H, Nose M, Hiai H, et al. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11:141–151.
   PubMed Web of Science ®Google Scholar
• Nishimura H, Okazaki T, Tanaka Y, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001;291:319–322.
   PubMed Web of Science ®Google Scholar
• Okazaki T, Tanaka Y, Nishio R, et al. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med. 2003;9:1477–1483.
   PubMed Web of Science ®Google Scholar
• Ansari MJ, Salama AD, Chitnis T, et al. The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med. 2003;198:63–69.
   PubMed Web of Science ®Google Scholar
• Wang J, Yoshida T, Nakaki F, et al. Establishment of NOD-Pdcd1-/- mice as an efficient animal model of type I diabetes. Proc Natl Acad Sci USA. 2005;102:11823–11828.
   PubMed Web of Science ®Google Scholar
• Zhu B, Guleria I, Khosroshahi A, et al. Differential role of programmed death-ligand 1 [corrected] and programmed death-ligand 2 [corrected] in regulating the susceptibility and chronic progression of experimental autoimmune encephalomyelitis. J Immunol. 2006;176:3480–3489.
   PubMed Web of Science ®Google Scholar
• Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–2454.
   PubMed Web of Science ®Google Scholar
• Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372:2521–2532.
   PubMed Web of Science ®Google Scholar
• Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018–2028.
   PubMed Web of Science ®Google Scholar
• Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–1271.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol. 2015;33:1430–1437.
   PubMed Web of Science ®Google Scholar
• Haanen J, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28:iv119–iv142.
   PubMed Web of Science ®Google Scholar
• Matsuda K, Miyoshi H, Hiraoka K, et al. Clinicopathological value of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) expression in synovium of patients with rheumatoid arthritis. Clin Exp Med. 2018;18:487–494.
   PubMed Web of Science ®Google Scholar
• Lo B, Abdel-Motal UM. Lessons from CTLA-4 deficiency and checkpoint inhibition. Curr Opin Immunol. 2017;49:14–19.
   PubMed Web of Science ®Google Scholar
• Schwab C, Gabrysch A, Olbrich P, et al. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects. J Allergy Clin Immunol. 2018;142:1932–1946.
   PubMed Web of Science ®Google Scholar
• Agarwal K, Jones DE, Daly AK, et al. CTLA-4 gene polymorphism confers susceptibility to primary biliary cirrhosis. J Hepatol. 2000;32:538–541.
   PubMed Web of Science ®Google Scholar
• Juran BD, Atkinson EJ, Schlicht EM, et al. Primary biliary cirrhosis is associated with a genetic variant in the 3' flanking region of the CTLA4 gene. Gastroenterology. 2008;135:1200–1206.
   PubMed Web of Science ®Google Scholar
• Juran BD, Atkinson EJ, Schlicht EM, et al. Interacting alleles of the coinhibitory immunoreceptor genes cytotoxic T-lymphocyte antigen 4 and programmed cell-death 1 influence risk and features of primary biliary cirrhosis. Hepatology. 2008;47:563–570.
   PubMed Web of Science ®Google Scholar
• Juran BD, Atkinson EJ, Larson JJ, et al. Carriage of a tumor necrosis factor polymorphism amplifies the cytotoxic T-lymphocyte antigen 4 attributed risk of primary biliary cirrhosis: evidence for a gene-gene interaction. Hepatology. 2010;52:223–229.
   PubMed Web of Science ®Google Scholar
• Agarwal K, Czaja AJ, Jones DE, et al. Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis. Hepatology. 2000;31:49–53.
   PubMed Web of Science ®Google Scholar
• Chaouali M, Carvalho A, Tezeghdenti A, et al. Cytotoxic T lymphocyte antigen-4 gene polymorphisms and susceptibility to type 1 autoimmune hepatitis in the Tunisian population. Genes Dis. 2018;5:256–262.
   PubMed Web of Science ®Google Scholar
• Kroner A, Mehling M, Hemmer B, et al. A PD-1 polymorphism is associated with disease progression in multiple sclerosis. Ann Neurol. 2005;58:50–57.
   PubMed Web of Science ®Google Scholar
• Prokunina L, Castillejo LC, Oberg F, et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet. 2002;32:666–669.
   PubMed Web of Science ®Google Scholar
• Nielsen C, Hansen D, Husby S, et al. Association of a putative regulatory polymorphism in the PD-1 gene with susceptibility to type 1 diabetes. Tissue Antigens. 2003;62:492–497.
   PubMed Web of Science ®Google Scholar
• Lin SC, Yen JH, Tsai JJ, et al. Association of a programmed death 1 gene polymorphism with the development of rheumatoid arthritis, but not systemic lupus erythematosus. Arthritis Rheum. 2004;50:770–775.
   PubMed Web of Science ®Google Scholar
• Nielsen C, Laustrup H, Voss A, et al. A putative regulatory polymorphism in PD-1 is associated with nephropathy in a population-based cohort of systemic lupus erythematosus patients. Lupus. 2004;13:510–516.
   PubMed Web of Science ®Google Scholar
• Oikawa T, Takahashi H, Ishikawa T, et al. Intrahepatic expression of the co-stimulatory molecules programmed death-1, and its ligands in autoimmune liver disease. Pathol Int. 2007;57:485–492.
   PubMed Web of Science ®Google Scholar
• Cao J, Liu FX, Yu MX. Expression of programmed death 1 and its ligands in the liver of autoimmune hepatitis C57BL/6 mice. Chin Med J. 2009;122:1941–1946.
   PubMed Web of Science ®Google Scholar
• Yi JS, Cox MA, Zajac AJ. T-cell exhaustion: characteristics, causes and conversion. Immunology. 2010;129:474–481.
   PubMed Web of Science ®Google Scholar
• Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12:492–499.
   PubMed Web of Science ®Google Scholar
• McKinney EF, Lee JC, Jayne DR, et al. T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. Nature. 2015;523:612–616.
   PubMed Web of Science ®Google Scholar
• Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15:486–499.
   PubMed Web of Science ®Google Scholar
• Wherry EJ, Ha SJ, Kaech SM, et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity. 2007;27:670–684.
   PubMed Web of Science ®Google Scholar
• Blackburn SD, Shin H, Haining WN, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009;10:29–37.
   PubMed Web of Science ®Google Scholar
• Crawford A, Angelosanto JM, Kao C, et al. Molecular and transcriptional basis of CD4(+) T cell dysfunction during chronic infection. Immunity. 2014;40:289–302.
   PubMed Web of Science ®Google Scholar
• Zarour HM. Reversing T-cell dysfunction and exhaustion in cancer. Clin Cancer Res. 2016;22:1856–1864.
   PubMed Web of Science ®Google Scholar
• Catakovic K, Klieser E, Neureiter D, et al. T cell exhaustion: from pathophysiological basics to tumor immunotherapy. Cell Commun Signal. 2017;15:1.
   PubMed Web of Science ®Google Scholar
• McKinney EF, Smith KG. T cell exhaustion and immune-mediated disease-the potential for therapeutic exhaustion. Curr Opin Immunol. 2016;43:74–80.
   PubMed Web of Science ®Google Scholar
• McKinney EF, Smith KG. T-cell exhaustion: understanding the interface of chronic viral and autoinflammatory diseases. Immunol Cell Biol. 2016;94:935–942.
   PubMed Web of Science ®Google Scholar
• Matsumoto K, Miyake Y, Matsushita H, et al. Anti-programmed cell death-1 antibody as a new serological marker for type 1 autoimmune hepatitis. J Gastroenterol Hepatol. 2014;29:110–115.
   PubMed Web of Science ®Google Scholar
• Miyake Y, Yamamoto K, Matsushita H, et al. Multicenter validation study of anti-programmed cell death-1 antibody as a serological marker for type 1 autoimmune hepatitis. Hepatol Res. 2014;44:1299–1307.
   PubMed Web of Science ®Google Scholar
• Reynolds J, Tam FW, Chandraker A, et al. CD28-B7 blockade prevents the development of experimental autoimmune glomerulonephritis. J Clin Invest. 2000;105:643–651.
   PubMed Web of Science ®Google Scholar
• Velu V, Titanji K, Zhu B, et al. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature. 2009;458:206–210.
   PubMed Web of Science ®Google Scholar
• McGee HS, Yagita H, Shao Z, et al. Programmed death-1 antibody blocks therapeutic effects of T-regulatory cells in cockroach antigen-induced allergic asthma. Am J Respir Cell Mol Biol. 2010;43:432–442.
   PubMed Web of Science ®Google Scholar
• Rosenblatt J, Glotzbecker B, Mills H, et al. PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell responses to autologous dendritic cell/myeloma fusion vaccine. J Immunother. 2011;34:409–418.
   PubMed Web of Science ®Google Scholar
• Wafula PO, Teles A, Schumacher A, et al. PD-1 but not CTLA-4 blockage abrogates the protective effect of regulatory T cells in a pregnancy murine model. Am J Reprod Immunol. 2009;62:283–292.
   PubMed Web of Science ®Google Scholar
• Bittencourt PL, Palacios SA, Cancado EL, et al. Cytotoxic T lymphocyte antigen-4 gene polymorphisms do not confer susceptibility to autoimmune hepatitis types 1 and 2 in Brazil. Am J Gastroenterol. 2003;98:1616–1620.
   PubMed Web of Science ®Google Scholar
• Korhonen R, Moilanen E. Abatacept, a novel CD80/86-CD28 T cell co-stimulation modulator, in the treatment of rheumatoid arthritis. Basic Clin Pharmacol Toxicol. 2009;104:276–284.
   PubMed Web of Science ®Google Scholar
• Finck BK, Linsley PS, Wofsy D. Treatment of murine lupus with CTLA4Ig. Science. 1994;265:1225–1227.
   PubMed Web of Science ®Google Scholar
• Webb LM, Walmsley MJ, Feldmann M. Prevention and amelioration of collagen-induced arthritis by blockade of the CD28 co-stimulatory pathway: requirement for both B7-1 and B7-2. Eur J Immunol. 1996;26:2320–2328.
   PubMed Web of Science ®Google Scholar
• Blazar BR, Taylor PA, Linsley PS, et al. In vivo blockade of CD28/CTLA4: B7/BB1 interaction with CTLA4-Ig reduces lethal murine graft-versus-host disease across the major histocompatibility complex barrier in mice. Blood. 1994;83:3815–3825.
   PubMed Web of Science ®Google Scholar
• Guo L, Fujino M, Kimura H, et al. Simultaneous blockade of co-stimulatory signals, CD28 and ICOS, induced a stable tolerance in rat heart transplantation. Transpl Immunol. 2003;12:41–48.
   PubMed Web of Science ®Google Scholar
• Kirk AD, Harlan DM, Armstrong NN, et al. CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates. Proc Natl Acad Sci USA. 1997;94:8789–8794.
   PubMed Web of Science ®Google Scholar
• Moreland LW, Alten R, Van den Bosch F, et al. 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. 2002;46:1470–1479.
   PubMed Web of Science ®Google Scholar
• Kremer JM, Westhovens R, Leon M, et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med. 2003;349:1907–1915.
   PubMed Web of Science ®Google Scholar
• Kremer JM, Dougados M, Emery P, et al. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 2005;52:2263–2271.
   PubMed Web of Science ®Google Scholar
• Goldzweig O, Hashkes PJ. Abatacept in the treatment of polyarticular JIA: development, clinical utility, and place in therapy. Drug Des Dev Ther. 2011;5:61–70.
   PubMed Web of Science ®Google Scholar
• Merrill JT, Burgos-Vargas R, Westhovens R, et al. The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2010;62:3077–3087.
   PubMed Web of Science ®Google Scholar
• Linsley PS, Greene JL, Brady W, et al. Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity. 1994;1:793–801.
   PubMed Web of Science ®Google Scholar
• Larsen CP, Pearson TC, Adams AB, et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant. 2005;5:443–453.
   PubMed Web of Science ®Google Scholar
• Archdeacon P, Dixon C, Belen O, et al. Summary of the US FDA approval of belatacept. Am J Transplant. 2012;12:554–562.
   PubMed Web of Science ®Google Scholar
• Vincenti F, Blancho G, Durrbach A, et al. Five-year safety and efficacy of belatacept in renal transplantation. J Am Soc Nephrol. 2010;21:1587–1596.
   PubMed Web of Science ®Google Scholar
• Krummey SM, Cheeseman JA, Conger JA, et al. High CTLA-4 expression on Th17 cells results in increased sensitivity to CTLA-4 coinhibition and resistance to belatacept. Am J Transplant. 2014;14:607–614.
   PubMed Web of Science ®Google Scholar
• Eagar TN, Karandikar NJ, Bluestone JA, et al. The role of CTLA-4 in induction and maintenance of peripheral T cell tolerance. Eur J Immunol. 2002;32:972–981.
   PubMed Web of Science ®Google Scholar
• Riella LV, Liu T, Yang J, et al. Deleterious effect of CTLA4-Ig on a Treg-dependent transplant model. Am J Transplant. 2012;12:846–855.
   PubMed Web of Science ®Google Scholar
• Linsley PS, Nadler SG. The clinical utility of inhibiting CD28-mediated costimulation. Immunol Rev. 2009;229:307–321.
   PubMed Web of Science ®Google Scholar
• Poirier N, Blancho G, Vanhove B. A more selective costimulatory blockade of the CD28-B7 pathway. Transpl Int. 2011;24:2–11.
   PubMed Web of Science ®Google Scholar
• Zhang T, Fresnay S, Welty E, et al. Selective CD28 blockade attenuates acute and chronic rejection of murine cardiac allografts in a CTLA-4-dependent manner. Am J Transplant. 2011;11:1599–1609.
   PubMed Web of Science ®Google Scholar
• Suchard SJ, Davis PM, Kansal S, et al. A monovalent anti-human CD28 domain antibody antagonist: preclinical efficacy and safety. JI. 2013;191:4599–4610.
   Google Scholar
• Salomon B, Lenschow DJ, Rhee L, et al. B7/CD28 costimulation is essential for the homeostasis of the CD4 + CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity. 2000;12:431–440.
   PubMed Web of Science ®Google Scholar
• Tang Q, Henriksen KJ, Boden EK, et al. Cutting edge: CD28 controls peripheral homeostasis of CD4 + CD25+ regulatory T cells. J Immunol. 2003;171:3348–3352.
   PubMed Web of Science ®Google Scholar
• Brooks DG, Ha SJ, Elsaesser H, et al. IL-10 and PD-L1 operate through distinct pathways to suppress T-cell activity during persistent viral infection. Proc Natl Acad Sci USA. 2008;105:20428–20433.
   PubMed Web of Science ®Google Scholar
• Parrish-Novak J, Foster DC, Holly RD, et al. Interleukin-21 and the IL-21 receptor: novel effectors of NK and T cell responses. J Leukoc Biol. 2002;72:856–863.
   PubMed Web of Science ®Google Scholar
• Bolduan S, Koppensteiner H, Businger R, et al. T cells with low CD2 levels express reduced restriction factors and are preferentially infected in therapy naive chronic HIV-1 patients. J Int AIDS Soc. 2017;20:21865.
   PubMed Web of Science ®Google Scholar
• Yi JS, Du M, Zajac AJ. A vital role for interleukin-21 in the control of a chronic viral infection. Science. 2009;324:1572–1576.
   PubMed Web of Science ®Google Scholar
• Majeau GR, Meier W, Jimmo B, et al. Mechanism of lymphocyte function-associated molecule 3-Ig fusion proteins inhibition of T cell responses. Structure/function analysis in vitro and in human CD2 transgenic mice. J Immunol. 1994;152:2753–2767.
   PubMed Web of Science ®Google Scholar
• da Silva AJ, Brickelmaier M, Majeau GR, et al. Alefacept, an immunomodulatory recombinant LFA-3/IgG1 fusion protein, induces CD16 signaling and CD2/CD16-dependent apoptosis of CD2(+) cells. J Immunol. 2002;168:4462–4471.
   PubMed Web of Science ®Google Scholar
• Miller GT, Hochman PS, Meier W, et al. Specific interaction of lymphocyte function-associated antigen 3 with CD2 can inhibit T cell responses. J Exp Med. 1993;178:211–222.
   PubMed Web of Science ®Google Scholar
• Chamian F, Lowes MA, Lin SL, et al. Alefacept reduces infiltrating T cells, activated dendritic cells, and inflammatory genes in psoriasis vulgaris. Proc Natl Acad Sci USA. 2005;102:2075–2080.
   PubMed Web of Science ®Google Scholar
• Rigby MR, Harris KM, Pinckney A, et al. Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients. J Clin Invest. 2015;125:3285–3296.
   PubMed Web of Science ®Google Scholar
• Kaplon H, Reichert JM. Antibodies to watch in 2019. MAbs. 2018;11:219–238.
   PubMed Web of Science ®Google Scholar
• Santos PM, Butterfield LH. Next steps for immune checkpoints in hepatocellular carcinoma. Gastroenterology. 2018;155:1684–1686.
   PubMed Web of Science ®Google Scholar
• Bucktrout SL, Bluestone JA, Ramsdell F. Recent advances in immunotherapies: from infection and autoimmunity, to cancer, and back again. Genome Med. 2018;10:79.
   PubMed Web of Science ®Google Scholar
• Wada H, Matsumoto N, Maenaka K, et al. The inhibitory NK cell receptor CD94/NKG2A and the activating receptor CD94/NKG2C bind the top of HLA-E through mostly shared but partly distinct sets of HLA-E residues. Eur J Immunol. 2004;34:81–90.
   PubMed Web of Science ®Google Scholar
• van Montfoort N, Borst L, Korrer MJ, et al. NKG2A blockade potentiates CD8 T cell immunity induced by cancer vaccines. Cell. 2018;175:1744–1755 e1715.
   PubMed Web of Science ®Google Scholar
• Haanen JB, Cerundolo V. NKG2A, a new kid on the immune checkpoint block. Cell. 2018;175:1720–1722.
   PubMed Web of Science ®Google Scholar
• Huard B, Tournier M, Hercend T, et al. Lymphocyte-activation gene 3/major histocompatibility complex class II interaction modulates the antigenic response of CD4+ T lymphocytes. Eur J Immunol. 1994;24:3216–3221.
   PubMed Web of Science ®Google Scholar
• Huard B, Prigent P, Tournier M, et al. CD4/major histocompatibility complex class II interaction analyzed with CD4- and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins. Eur J Immunol. 1995;25:2718–2721.
   PubMed Web of Science ®Google Scholar
• Huang CT, Workman CJ, Flies D, et al. Role of LAG-3 in regulatory T cells. Immunity. 2004;21:503–513.
   PubMed Web of Science ®Google Scholar
• Dixon KO, Schorer M, Nevin J, et al. Functional anti-TIGIT antibodies regulate development of autoimmunity and antitumor immunity. JI. 2018;200:3000–3007.
   Google Scholar
• Xu W, Hiếu T, Malarkannan S, et al. The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation. Cell Mol Immunol. 2018;15:438–446.
   PubMed Web of Science ®Google Scholar
• Monney L, Sabatos CA, Gaglia JL, et al. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature. 2002;415:536–541.
   PubMed Web of Science ®Google Scholar
• Dardalhon V, Anderson AC, Karman J, et al. Tim-3/galectin-9 pathway: regulation of Th1 immunity through promotion of CD11b + Ly-6G + myeloid cells. JI. 2010;185:1383–1392.
   Google Scholar