A Comprehensive Review on T Cells, B Cells, Natural Killer Cells, and Dendritic Cells Exhaustion: From Main Concepts to Clinical Use
Abstract
During chronic infections, a distinct physiological condition named “exhaustion” arises that is associated with the dysfunctionality in immune cells and their eventual removal from the environment, which evidently help the progress of infection or tumors in human or animal bodies. This state of immune cells could be under the control of different elements such as the antigen load, help from inhibitory cells, lack of costimulatory signals and etc. Exhaustion that has been found in different immune system cells, is usually accompanied by impaired effector function and proliferation of immune cells, poor memory recall, upregulation of inhibitory molecules, compromised metabolism and altered transcription program, and is considered a reversible process, unlike other physiological states like anergy or senescence, organized through the blockage of several factors. Although the emergence of these cells in viral infections and cancer is an undesirable event, the importance of the presence of exhausted cells in autoimmune diseases and organ transplantation is highlighted as a positive change. In this review, we aimed to determine the occurrence of this process in different immune cells, the characteristics obtained by these cells, effective and primitive factors on exhaustion, metabolic and transcriptional cell changes, and the use of these cells in autoimmune diseases and organ transplantation.
2. Bi J, Tian Z. NK Cell Exhaustion. Frontiers in immunology 2017;8:760.
3. Crespo J, Sun H, Welling TH, Tian Z, Zou W. T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr Opin Immunol 2013;25:214-21.
4. Jiang Y, Li Y, Zhu B. T-cell exhaustion in the tumor microenvironment. Cell Death Dis 2015;6:e1792.
5. Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol 2003;77:4911-27.
6. Moir S, Fauci AS. B-cell exhaustion in HIV infection: the role of immune activation. Curr Opin HIV AIDS 2014;9:472-7.
7. Ebihara T, Taniuchi I. Exhausted-like Group 2 Innate Lymphoid Cells in Chronic Allergic Inflammation. Trends Immunol 2019;40:1095-104.
8. Macal M, Lewis GM, Kunz S, Flavell R, Harker JA, Zuñiga EI. Plasmacytoid dendritic cells are productively infected and activated through TLR-7 early after arenavirus infection. Cell Host Microbe 2012;11:617-30.
9. Kasakovski D, Xu L, Li Y. T cell senescence and CAR-T cell exhaustion in hematological malignancies. J Hematol Oncol 2018;11:91.
10. Sterzl J, Silverstein AM. Developmental Aspects of Immunity. Adv Immunol 1967;6:337-459.
11. Moskophidis D, Lechner H, Pircher H, Rolf M, Zinkernagel RM. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 1993;362:758-61.
12. Goepfert PA, Bansal A, Edwards BH, Ritter Jr GD, Tellez I, McPherson SA, et al. A significant number of human immunodeficiency virus epitope-specific cytotoxic T lymphocytes detected by tetramer binding do not produce gamma interferon. J Virol 2000;74:10249-55.
13. Schlaak JF, Tully G, Löhr HF, Gerken G, Meyer zum Büschenfelde KH. The presence of high amounts of HBV-DNA in serum is associated with suppressed costimulatory effects of interleukin 12 on HBV-induced immune response. J Hepatol 1999;30:353-8.
14. Gruener NH, Lechner F, Jung MC, Diepolder H, Gerlach T, Lauer G, et al. Sustained dysfunction of antiviral CD8+ T lymphocytes after infection with hepatitis C virus. J Virol 2001;75:5550-8.
15. Greten TF, Slansky JE, Kubota R, Soldan SS, Jaffee EM, Leist TP, et al. Direct visualization of antigen-specific T cells: HTLV-1 Tax11-19- specific CD8(+) T cells are activated in peripheral blood and accumulate in cerebrospinal fluid from HAM/TSP patients. Proc Natl Acad Sci U S A 1998;95:7568-73.
16. Day CL, Abrahams DA, Lerumo L, Janse van Rensburg E, Stone L, O'rie T, et al. Functional capacity of Mycobacterium tuberculosis-specific T cell responses in humans is associated with mycobacterial load. J Immunol 2011;187:2222-32.
17. Davoodzadeh Gholami M, Kardar GA, Saeedi Y, Heydari S, Garssen J, Falak R. Exhaustion of T lymphocytes in the tumor microenvironment: Significance and effective mechanisms. Cell Immunol 2017;322:1-14.
18. Klocperk A, Unger S, Friedmann D, Seidl M, Zoldan K, Pfeiffer J, et al. Exhausted phenotype of follicular CD8 T cells in CVID. J Allergy Clin Immunol 2020;146:912-15.e13.
19. Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 2009;10:29-37.
20. Bengsch B, Johnson AL, Kurachi M, Odorizzi PM, Pauken KE, Attanasio J, et al. Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8(+) T Cell Exhaustion. Immunity 2016;45:358-73.
21. Kahan SM, Wherry EJ, Zajac AJ. T cell exhaustion during persistent viral infections. Virology 2015;479-80:180-93.
22. Brooks DG, Teyton L, Oldstone MB, McGavern DB. Intrinsic functional dysregulation of CD4 T cells occurs rapidly following persistent viral infection. J Virol 2005;79:10514-27.
23. Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nature reviews. Nat Rev Immunol 2015;15:486-99.
24. Crawford A, Angelosanto JM, Kao C, Doering TA, Odorizzi PM, Barnett BE, et al. Molecular and transcriptional basis of CD4(+) T cell dysfunction during chronic infection. Immunity 2014;40:289-302.
25. van der Werf N, Redpath SA, Azuma M, Yagita H, Taylor MD. Th2 cell-intrinsic hypo-responsiveness determines susceptibility to helminth infection. PLoS pathogens 9, e1003215 (2013).
26. 26. J. A. Knipper, A. Ivens, M. D. Taylor, Helminth-induced Th2 cell dysfunction is distinct from exhaustion and is maintained in the absence of antigen. PLoS Pathog 2013;9:e1003215.
27. Brahmi Z, Bray RA, Abrams SI. Evidence for an early calcium-independent event in the activation of the human natural killer cell cytolytic mechanism. J Immunol 1985;135:4108-13.
28. Smyth MJ, Cretney E, Takeda K, Wiltrout RH, Sedger LM, Kayagaki N, et al. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) contributes to interferon gamma-dependent natural killer cell protection from tumor metastasis. J Exp Med 2001;193:661-70.
29. Hasmim M, Messai Y, Ziani L, Thiery J, Bouhris JH, Noman MZ, et al. Critical Role of Tumor Microenvironment in Shaping NK Cell Functions: Implication of Hypoxic Stress. Front Immunol 2015;6:482.
30. Peng YP, Zhu Y, Zhang JJ, Xu ZK, Qian ZY, Dai CC, et al. Comprehensive analysis of the percentage of surface receptors and cytotoxic granules positive natural killer cells in patients with pancreatic cancer, gastric cancer, and colorectal cancer. J Transl Med 2013;11:262.
31. De Maria A, Fogli M, Costa P, Murdaca G, Puppo F, Mavilio D, et al. The impaired NK cell cytolytic function in viremic HIV-1 infection is associated with a reduced surface expression of natural cytotoxicity receptors (NKp46, NKp30 and NKp44). Eur J Immunol 2003;33:2410-8.
32. Meier UC, Owen RE, Taylor E, Worth A, Naoumov N, Willberg C, et al., Shared alterations in NK cell frequency, phenotype, and function in chronic human immunodeficiency virus and hepatitis C virus infections. J Virol 2005;79:12365-74.
33. Sun C, Fu B, Gao Y, Liao X, Sun R, Tian Z, et al. TGF-beta1 down-regulation of NKG2D/DAP10 and 2B4/SAP expression on human NK cells contributes to HBV persistence. PLoS Pathog 2012;8:e1002594.
34. Shifrin N, Raulet DH, Ardolino M. NK cell self-tolerance, responsiveness and missing self-recognition. Semin Immunol 2014;26:138-44.
35. Felices M, Lenvik AJ, McElmurry R, Chu S, Hinderlie P, Bendzick L, et al. Continuous treatment with IL-15 exhausts human NK cells via a metabolic defect. JCI Insight 2018;3:e96219.
36. Sun H, Huang Q, Huang M, Wen H, Lin R, Zheng M, et al. Human CD96 Correlates to Natural Killer Cell Exhaustion and Predicts the Prognosis of Human Hepatocellular Carcinoma. Hepatology 2019;70:168-83.
37. Moir S, Ho J, Malaspina A, Wang W, DiPoto AC, O'Shea MA, et al. Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals J Exp Med 2008;205:1797-805.
38. Khoder A, Alsuliman A, Basar R, Sobieski C, Kondo K, Alousi AM, et al. Evidence for B Cell Exhaustion in Chronic Graft-versus-Host Disease. Front Immunol 2017;8:1937.
39. Holla P, Ambegaonkar A, Sohn H, Pierce SK. Exhaustion may not be in the human B cell vocabulary, at least not in malaria. Immunol Rev 2019;292:139-48.
40. Collin M, Bigley V. Human dendritic cell subsets: an update. Immunology 2018;154:3-20.
41. Kajino K, Nakamura I, Bamba H, Sawai T, Ogasawara K. Involvement of IL-10 in exhaustion of myeloid dendritic cells and rescue by CD40 stimulation. Immunology 2007;120:28-37.
42. Bergthaler A, Flatz L, Hegazy AN, Johnson S, Horvath E, Löhning M, et al. Viral replicative capacity is the primary determinant of lymphocytic choriomeningitis virus persistence and immunosuppression. Proc Natl Acad Sci U S A. 2010;107:21641-6.
43. Duan XZ, Wang M, Li HW, Zhuang H, Xu D, Wang FS. Decreased frequency and function of circulating plasmocytoid dendritic cells (pDC) in hepatitis B virus infected humans. J Clin Immunol 2004;24:637-46.
44. Lee LN, Burke S, Montoya M, Borrow P. Multiple mechanisms contribute to impairment of type 1 interferon production during chronic lymphocytic choriomeningitis virus infection of mice. J Immunol 2009;182:7178-89.
45. Kanto T, Inoue M, Miyatake H, Sato A, Sakakibara M, Yakushijin T, et al. Reduced numbers and impaired ability of myeloid and plasmacytoid dendritic cells to polarize T helper cells in chronic hepatitis C virus infection. J Infect Dis 2004;190:1919-26.
46. Labidi-Galy SI, Sisirak V, Meeus P, Gobert M, Treilleux I, Bajard A, et al. Quantitative and functional alterations of plasmacytoid dendritic cells contribute to immune tolerance in ovarian cancer. Cancer Res 2011;71:5423-34.
47. Macal M, Jo Y, Dallari S, Chang AY, Dai J, Swaminathan S, et al., Self-Renewal and Toll-like Receptor Signaling Sustain Exhausted Plasmacytoid Dendritic Cells during Chronic Viral Infection. Immunity 2018;48:730-44.e5.
48. Boni C, Fisicaro P, Valdatta C, Amadei B, Di Vincenzo P, Giuberti T, et al. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J Virol 2007;81:4215-25.
49. Belz GT, Xie W, Altman JD, Doherty PC. A previously unrecognized H-2D(b)-restricted peptide prominent in the primary influenza A virus-specific CD8(+) T-cell response is much less apparent following secondary challenge. J Virol 2000;74:3486-93.
50. Blattman JN, Wherry EJ, Ha SJ, van der Most RG, Ahmed R. Impact of epitope escape on PD-1 expression and CD8 T-cell exhaustion during chronic infection. J Virol 2009;83:4386-94.
51. Shin H, Wherry EJ. CD8 T cell dysfunction during chronic viral infection. Curr Opin Immunol. 2007;19:408-15.
52. Abel AM, Yang C, Thakar MS, Malarkannan S. Natural Killer Cells: Development, Maturation, and Clinical Utilization. Front Immunol 2018;9:1869.
53. Cook KD, Whitmire JK. The depletion of NK cells prevents T cell exhaustion to efficiently control disseminating virus infection. 53. Cook KD, Whitmire JK. The depletion of NK cells prevents T cell exhaustion to efficiently control disseminating virus infection. J Immunol 2013;190:641-9.
54. Cook KD, Waggoner SN, Whitmire JK. NK cells and their ability to modulate T cells during virus infections. Crit Rev Immunol 2014;34:359-88.
55. Gray JD HM, Ohtsuka K, Horwitz DA. Generation of an inhibitory circuit involving CD8+ T cells, IL-2, and NK cell-derived TGF-beta: contrasting effects of anti-CD2 and anti-CD3. J Immunol 1998;160:2248-54.
56. Cerboni C, Zingoni A, Cippitelli M, Piccoli M, Frati L, Santoni A. Antigen-activated human T lymphocytes express cell-surface NKG2D ligands via an ATM/ATR-dependent mechanism and become susceptible to autologous NK- cell lysis. Blood 2007;110:606-15.
57. Barber MA, Zhang T, Gagne BA, Sentman CL. NK cells negatively regulate antigen presentation and tumor-specific CTLs in a syngeneic lymphoma model. J Immunol 2007;178:6140-7.
58. Ahrends T, Busselaar J, Severson TM, Babala N, de Vries E, Bovens A, et al. CD4(+) T cell help creates memory CD8(+) T cells with innate and help-independent recall capacities. Nat Commun 2019;10:5531.
59. Bedoui S, Heath WR, Mueller SN. CD4(+) T-cell help amplifies innate signals for primary CD8(+) T-cell immunity. Immunol Rev 2016;272:52-64.
60. Bourgeois C, Rocha B, Tanchot C. A role for CD40 expression on CD8+ T cells in the generation of CD8+ T cell memory. Science 2002;297:2060-3.
61. Cox MA, Kahan SM, Zajac AJ. Anti-viral CD8 T cells and the cytokines that they love. Virology 2013;435:157-69.
62. Matloubian M, Concepcion RJ, Ahmed R. CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J Virol 1994;68:8056-63.
63. Laidlaw BJ, Craft JE, Kaech SM. The multifaceted role of CD4(+) T cells in CD8(+) T cell memory. Nat Rev Immunol 2016;16:102-11.
64. Bachmann MF, Wolint P, Walton S, Schwarz K, Oxenius A. Differential role of IL-2R signaling for CD8+ T cell responses in acute and chronic viral infections. Eur J Immunol 2007;37:1502-12.
65. Chevalier MF, Julg B, Pyo A, Flanders M, Ranasinghe S, Soghoian DZ, et al. HIV-1-specific interleukin-21+ CD4+ T cell responses contribute to durable viral control through the modulation of HIV-specific CD8+ T cell function. J Virol 2011;85:733-41.
66. Romano M, Fanelli G, Albany CJ, Giganti G, Lombardi G. Past, Present, and Future of Regulatory T Cell Therapy in Transplantation and Autoimmunity. Front Immunol 2019;10:43.
67. Penaloza-MacMaster P, Kamphorst AO, Wieland A, Araki K, Iyer SS, West EE, et al. Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection. J Exp Med 2014;211:1905-18.
68. Borst J, Ahrends T, Babala N, Melief CJM, Kastenmuller W. CD4(+) T cell help in cancer immunology and immunotherapy. Nat Rev Immunol 2018;18:635-47.
69. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 2005;6:1142-51.
70. Sawant DV, Yano H, Chikina M, Zhang Q, Liao M, Liu C, et al. Adaptive plasticity of IL-10(+) and IL-35(+) Treg cells cooperatively promotes tumor T cell exhaustion. Nat Immunol 2019;20:724-35.
71. Topalian SL, Taube JM, Anders RA, Pardoll DM. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 2016;16:275-87.
72. Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 2004;4:762-742.
73. Kim HJ, Wang X, Radfar S, Sproule TJ, Roopenian DC, Cantor H. CD8+ T regulatory cells express the Ly49 Class I MHC receptor and are defective in autoimmune prone B6-Yaa mice. Proc Natl Acad Sci U S A 2011;108:2010-5.
74. Holderried TA, Lang PA, Kim HJ, Cantor H. Genetic disruption of CD8+ Treg activity enhances the immune response to viral infection. Proc Natl Acad Sci U S A 2013;110:21089-94.
75. Ng CT, Snell LM, Brooks DG, Oldstone MB. Networking at the level of host immunity: immune cell interactions during persistent viral infections. Cell Host Microbe 2013;13:652-64.
76. Ladell K, Hashimoto M, Iglesias MC, Wilmann PG, McLaren JE, Gras S, et al. A molecular basis for the control of preimmune escape variants by HIV-specific CD8+ T cells. Immunity 2013;38:425-36.
77. Fitzgerald-Bocarsly P, Jacobs ES. Plasmacytoid dendritic cells in HIV infection: striking a delicate balance. J Leukoc Biol 2010;87:609-20.
78. Wilson EB, Kidani Y, Elsaesser H, Barnard J, Raff L, Karp CL, et al. Emergence of distinct multiarmed immunoregulatory antigen-presenting cells during persistent viral infection. Cell Host Microbe 2012;11:481-91.
79. Veglia F, Gabrilovich DI. Dendritic cells in cancer: the role revisited. Curr Opin Immunol 2017;45:43-51.
80. Blair PA, Norena LY, Flores-Borja F, Rawlings DJ, Isenberg DA, Ehrenstein MR, et al. CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients. Immunity 2010;32:129-40.
81. Olkhanud PB, Damdinsuren B, Bodogai M, Gress RE, Sen R, Wejksza K, et al. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4(+) T cells to T-regulatory cells. Cancer Res 2011;71:3505-15.
82. Das A, Ellis G, Pallant C, Lopes AR, Khanna P, Peppa D, et al. IL-10-producing regulatory B cells in the pathogenesis of chronic hepatitis B virus infection. J Immunol 2012;189:3925-35.
83. Menon M, Blair PA, Isenberg DA, Mauri C. A Regulatory Feedback between Plasmacytoid Dendritic Cells and Regulatory B Cells Is Aberrant in Systemic Lupus Erythematosus. Immunity 2016;44:683-97.
84. Siewe B, Stapleton JT, Martinson J, Keshavarzian A, Kazmi N, Demarais PM, et al. Regulatory B cell frequency correlates with markers of HIV disease progression and attenuates anti-HIV CD8(+) T cell function in vitro. JJ Leukoc Biol 2013;93:811-8.
85. Nouel A, Pochard P, Simon Q, Segalen I, Le Meur Y, Pers JO, et al. B-Cells induce regulatory T cells through TGF-beta/IDO production in A CTLA-4 dependent manner. J Autoimmun 2015;59:53-60.
86. Ruytinx P, Proost P, Van Damme J, Struyf S. Chemokine-Induced Macrophage Polarization in Inflammatory Conditions. Front Immunol 2018;9:1930.
87. Brockman MA, Kwon DS, Tighe DP, Pavlik DF, Rosato PC, Sela J, et al. IL-10 is up-regulated in multiple cell types during viremic HIV infection and reversibly inhibits virus-specific T cells. Blood 2009;114:346-56.
88. Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity 2014;41:49-61.
89. Wu AA, Drake V, Huang HS, Chiu S, Zheng L. Reprogramming the tumor microenvironment: tumor-induced immunosuppressive factors paralyze T cells. Oncoimmunology 2015;4:e1016700.
90. Rodriguez PC, Zea AH, Culotta KS, Zabaleta J, Ochoa JB, Ochoa AC. Regulation of T cell receptor CD3zeta chain expression by L-arginine. J Biol Chem 2002;277:21123-9.
91. Goh C, Narayanan S, Hahn YS. Myeloid-derived suppressor cells: the dark knight or the joker in viral infections? Immunol Rev 2013;255:210-21.
92. Cai W, Qin A, Guo P, Yan D, Hu F, Yang Q, et al. Clinical significance and functional studies of myeloid-derived suppressor cells in chronic hepatitis C patients. J Clin Immunol 2013;33:798-808.
93. Qin A, Cai W, Pan T, Wu K, Yang Q, Wang N, et al. Expansion of monocytic myeloid-derived suppressor cells dampens T cell function in HIV-1-seropositive individuals. J Virol 2013;87:1477-90.
94. Batlle E, Massague J. Transforming Growth Factor-beta Signaling in Immunity and Cancer. Immunity 2019;50:924-40.
95. Brabletz T, et al. Transforming growth factor beta and cyclosporin A inhibit the inducible activity of the interleukin-2 gene in T cells through a noncanonical octamer-binding site. Mol Cell Biol 1993;13:1155-62.
96. Thomas DA, Massague J. TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 2005;8:369-80.
97. Yu J, Wei M, Becknell B, Trotta R, Liu S, Boyd Z, et al. Pro- and antiinflammatory cytokine signaling: reciprocal antagonism regulates interferon-gamma production by human natural killer cells. Immunity 2006;24:575-90.
98. Castriconi R, Cantoni C, Della Chiesa M, Vitale M, Marcenaro E, Conte R, et al. Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. Proc Natl Acad Sci U S A 2003;100:4120-5.
99. Donatelli SS, Zhou JM, Gilvary DL, Eksioglu EA, Chen X, Cress WD, et al. TGF-beta-inducible microRNA-183 silences tumor-associated natural killer cells. Proc Natl Acad Sci U S A 2014;111:4203-8.
100. Petit-Koskas E, Genot E, Lawrence D, Kolb JP. Inhibition of the proliferative response of human B lymphocytes to B cell growth factor by transforming growth factor-beta. Eur J Immunol 1988;18:111-6.
101. Kehrl JH RA, Wakefield LM, Jakowlew S, Sporn MB, Fauci AS. Transforming growth factor beta is an important immunomodulatory protein for human B lymphocytes. J Immunol 1986;137:3855-60.
102. Papaspyridonos M, Matei I, Huang Y, do Rosario Andre M, Brazier-Mitouart H, Waite JC, et al. Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation. Nat Commun 2015;6:6840.
103. Wang X, He Q, Shen H, Xia A, Tian W, Yu W, et al. TOX promotes the exhaustion of antitumor CD8(+) T cells by preventing PD1 degradation in hepatocellular carcinoma. J Hepatol 2019;71:731-41.
104. Mannino MH, Zhu Z, Xiao H, Bai Q, Wakefield MR, Fang Y. The paradoxical role of IL-10 in immunity and cancer. Cancer lett 2015;367:103-7.
105. Couper KN, Blount DG, Riley EM. IL-10: the master regulator of immunity to infection. J Immunol 2008;180:5771-7.
106. Blackburn SD, Wherry EJ. IL-10, T cell exhaustion and viral persistence. Trends Microbiol 2007;15:143-6.
107. Lauw FN, Pajkrt D, Hack CE, Kurimoto M, van Deventer SJ, van der Poll T. Proinflammatory effects of IL-10 during human endotoxemia. J Immunol 2000;165:2783-9.
108. Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001;19:683-765.
109. Parish IA, Marshall HD, Staron MM, Lang PA, Brustle A, Chen JH, et al. Chronic viral infection promotes sustained Th1-derived immunoregulatory IL-10 via BLIMP-1. J Clin Invest 2014;124:3455-68.
110. Li L, Ma Y, Xu Y. Follicular regulatory T cells infiltrated the ovarian carcinoma and resulted in CD8 T cell dysfunction dependent on IL-10 pathway. Int Immunopharmacol 2019;68:81-7.
111. Ni G, Wang T, Walton S, Zhu B, Chen S, Wu X, et al. Manipulating IL-10 signalling blockade for better immunotherapy. Cell Immunol 2015;293:126-9.
112. Brooks DG, Ha SJ, Elsaesser H, Sharpe AH, Freeman GJ, Oldstone MB. IL-10 and PD-L1 operate through distinct pathways to suppress T-cell activity during persistent viral infection. Proc Natl Acad Sci U S A 2008;105:20428-33.
113. Dhupkar P, Gordon N. Interleukin-2: Old and New Approaches to Enhance Immune-Therapeutic Efficacy. Adv Exp Med Biol 2017;995:33-51.
114. Rosenberg SA, Mule JJ, Spiess PJ, Reichert CM, Schwarz SL. Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2. J Exp Med 1985;161:1169-88.
115. Hu CY, Zhang YH, Wang T, Chen L, Gong ZH, Wan YS, et al. Interleukin-2 reverses CD8(+) T cell exhaustion in clinical malignant pleural effusion of lung cancer. Clin Exp Immunol 2016;186:106-14.
116. Liu X, Li F, Niu H, Ma L, Chen J, Zhang Y, et al. IL-2 Restores T-Cell Dysfunction Induced by Persistent Mycobacterium tuberculosis Antigen Stimulation. Front Immunol 2019;10:2350.
117. Beltra JC, Bourbonnais S, Bedard N, Charpentier T, Boulange M, Michaud E, et al. IL2Rbeta-dependent signals drive terminal exhaustion and suppress memory development during chronic viral infection. PProc Natl Acad Sci U S A 2016;113:E5444-53.
118. Shourian M, Beltra JC, Bourdin B, Decaluwe H. Common gamma chain cytokines and CD8 T cells in cancer. Semin Immunol 2019;42:101307.
119. Bradley LM, Haynes L, Swain SL. IL-7: maintaining T-cell memory and achieving homeostasis. Trends Immunol 2005;26:172-6.
120. Takada K, Jameson SC. Naive T cell homeostasis: from awareness of space to a sense of place. Nat Rev Immunol 2009;9:823-32.
121. Jiang Q, Li WQ, Aiello FB, Mazzucchelli R, Asefa B, Khaled AR, et al. Cell biology of IL-7, a key lymphotrophin. Cytokine Growth Factor Rev 2005;16:513-33.
122. Lang KS, Recher M, Navarini AA, Harris NL, Lohning M, Junt T, et al. Inverse correlation between IL-7 receptor expression and CD8 T cell exhaustion during persistent antigen stimulation. Eur J Immunol 2005;35:738-45.
123. Levy Y, Lacabaratz C, Weiss L, Viard JP, Goujard C, Lelievre JD, et al. Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment. J Clin Invest 2009;119:997-1007.
124. Colombetti S, Levy F, Chapatte L. IL-7 adjuvant treatment enhances long-term tumor-antigen-specific CD8+ T-cell responses after immunization with recombinant lentivector. Blood 2009;113:6629-37.
125. He C, Zhou Y, Li Z, Farooq MA, Ajmal I, Zhang H, et al. Co-Expression of IL-7 Improves NKG2D-Based CAR T Cell Therapy on Prostate Cancer by Enhancing the Expansion and Inhibiting the Apoptosis and Exhaustion. Cancers (Basel) 2020;12:1969.
126. Pellegrini M, Calzascia T, Elford AR, Shahinian A, Lin AE, Dissanayake D, et al. Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies. Nat Med 2009;15:528-36.
127. Mishra A, Sullivan L, Caligiuri MA. Molecular pathways: interleukin-15 signaling in health and in cancer. Clin Cancer Res 2014;20:2044-50.
128. Kennedy MK, Glaccum M, Brown SN, Butz EA, Viney JL, Embers M, et al. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J Exp Med 2000;191:771-80.
129. Shenoy AR, Kirschnek S, Hacker G. IL-15 regulates Bcl-2 family members Bim and Mcl-1 through JAK/STAT and PI3K/AKT pathways in T cells. Eur J Immunol 2014;44:2500-7.
130. Klebanoff CA, Finkelstein SE, Surman DR, Lichtman MK, Gattinoni L, Theoret MR, et al. IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T cells. Proc Natl Acad Sci U S A 2004;101:1969-74.
131. Alizadeh D, Wong RA, Yang X, Wang D, Pecoraro JR, Kuo CF, et al. IL15 Enhances CAR-T Cell Antitumor Activity by Reducing mTORC1 Activity and Preserving Their Stem Cell Memory Phenotype. Cancer Immunol Res 2019;7:759-72.
132. Saito M, Inoue S, Yamashita K, Kakeji Y, Fukumoto T, Kotani J. IL-15 Improves Aging-Induced Persistent T Cell Exhaustion in Mouse Models of Repeated Sepsis. Shock 2020;53:228-35.
133. Spolski R, Leonard WJ. Interleukin-21: a double-edged sword with therapeutic potential. Nat Rev Drug Discov 2014;13:379-95.
134. Liu S, Lizee G, Lou Y, Liu C, Overwijk WW, Wang G, et al. IL-21 synergizes with IL-7 to augment expansion and anti-tumor function of cytotoxic T cells. Int Immunol 2007;19:1213-21.
135. Cui W, Liu Y, Weinstein JS, Craft J, Kaech SM. An interleukin-21-interleukin-10-STAT3 pathway is critical for functional maturation of memory CD8+ T cells. Immunity 2011;35:792-805.
136. Elsaesser H, Sauer K, Brooks DG. IL-21 is required to control chronic viral infection. Science 2009;324:1569-72.
137. Frohlich A, Kisielow J, Schmitz I, Freigang S, Shamshiev AT, Weber J, et al. IL-21R on T cells is critical for sustained functionality and control of chronic viral infection. Science 2009;324:1576-80.
138. Loschinski R, Bottcher M, Stoll A, Bruns H, Mackensen A, Mougiakakos D. IL-21 modulates memory and exhaustion phenotype of T-cells in a fatty acid oxidation-dependent manner. Oncotarget 2018;9:13125-38.
139. Hermans D, Gautam S, Garcia-Canaveras JC, Gromer D, Mitra S, Spolski R, et al. Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8(+) T cell stemness and antitumor immunity. Proc Natl Acad Sci U S A 2020;117:6047-55.
140. Moroz A, Eppolito C, Li Q, Tao J, Clegg CH, Shrikant PA. IL-21 enhances and sustains CD8+ T cell responses to achieve durable tumor immunity: comparative evaluation of IL-2, IL-15, and IL-21. J Immunol 2004;173:900-9.
141. Wang LN CY, Ruge F, Jiang WG. Interleukin 21 and Its Receptor Play a Role in Proliferation, Migration and Invasion of Breast Cancer Cells. Cancer Genomics Proteomics 2015;12:211-21.
142. Ueda M, Imada K, Imura A, Koga H, Hishizawa M, Uchiyama T. Expression of functional interleukin-21 receptor on adult T-cell leukaemia cells. Br J Haematol 2005;128:169-76.
143. Lamprecht B, Kreher S, Anagnostopoulos I, Johrens K, Monteleone G, Jundt F, et al. Aberrant expression of the Th2 cytokine IL-21 in Hodgkin lymphoma cells regulates STAT3 signaling and attracts Treg cells via regulation of MIP-3alpha. Blood 2008;112:3339-47.
144. Brenne AT, Ro TB, Waage A, Sundan A, Borset M, Hjorth-Hansen H. Interleukin-21 is a growth and survival factor for human myeloma cells. Blood 2002;99:3756-62.
145. Suprunenko T, Hofer MJ. Complexities of Type I Interferon Biology: Lessons from LCMV. Viruses 2019;11:172.
146. McNab F, Mayer-Barber K, Sher A, Wack A, O'Garra A. Type I interferons in infectious disease. Nat Rev Immunol 2015;15:87-103.
147. Wu T, Ji Y, Moseman EA, Xu HC, Manglani M, Kirby M, et al. The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness. Sci Immunol 2016;1:eaai8593.
148. Lee MS, Park CH, Jeong YH, Kim YJ, Ha SJ. Negative regulation of type I IFN expression by OASL1 permits chronic viral infection and CD8(+) T-cell exhaustion. PLoS Pathog 2013;9:e1003478.
149. Quigley M, Pereyra F, Nilsson B, Porichis F, Fonseca C, Eichbaum Q, et al. Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nat Med 2010;16:1147-51.
150. Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 2007;27:111-22.
151. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2006;439:682-7.
152. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008;26:677-704.
153. Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, Hashimoto-Tane A, Azuma M, Saito T. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med 2012;209:1201-17.
154. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol 2004;173:945-54.
155. Odorizzi PM, Pauken KE, Paley MA, Sharpe A, Wherry EJ. Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells. J Exp Med 2015;212:1125-37.
156. Fife BT, Pauken KE, Eagar TN, Obu T, Wu J, Tang Q, et al. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol 2009;10:1185-92.
157. Arasanz H, Gato-Canas M, Zuazo M, Ibanez-Vea M, Breckpot K, Kochan G, et al. PD1 signal transduction pathways in T cells. Oncotarget 2017;8:51936-45.
158. Fourcade J, Sun Z, Pagliano O, Guillaume P, Luescher IF, Sander C, et al. CD8(+) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1. Cancer Res 2012;72:887-96.
159. Curran MA, Montalvo W, Yagita H, Allison JP. 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 2010;107:4275-80.
160. Hannier S TM, Bismuth G, Triebel F. CD3/TCR complex-associated lymphocyte activation gene-3 molecules inhibit CD3/TCR signaling. J Immunol 1998;161:4058-65.
161. Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A, Tsuji T, et al. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci U S A 2010;107:7875-80.
162. Richter K, Agnellini P, Oxenius A. On the role of the inhibitory receptor LAG-3 in acute and chronic LCMV infection. Int Immunol 2010;22:13-23.
163. Dong Y, Li X, Zhang L, Zhu Q, Chen C, Bao J, et al. CD4(+) T cell exhaustion revealed by high PD-1 and LAG-3 expression and the loss of helper T cell function in chronic hepatitis B. BMC Immunol 2019;20:27.
164. Yang ZZ, Kim HJ, Villasboas JC, Chen YP, Price-Troska T, Jalali S, et al. Expression of LAG-3 defines exhaustion of intratumoral PD-1(+) T cells and correlates with poor outcome in follicular lymphoma. Oncotarget. 2017;8:61425-39.
165. Cao H, Zhang R, Zhang W. CTLA4 interferes with the HBVspecific T cell immune response (Review). Int J Mol Med 2018;42:703-12.
166. Egen JG, Kuhns MS, Allison JP. CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol 2002;3:611-8.
167. Romano E, Kusio-Kobialka M, Foukas PG, Baumgaertner P, Meyer C, Ballabeni P, et al. Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. 167. Romano E, Kusio-Kobialka M, Foukas PG, Baumgaertner P, Meyer C, Ballabeni P, et al. Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. Proc Natl Acad Sci U S A 2015;112:6140-5.
168. Ruocco MG, Pilones KA, Kawashima N, Cammer M, Huang J, Babb JS, et al. Suppressing T cell motility induced by anti-CTLA-4 monotherapy improves antitumor effects. J Clin Invest 2012;122:3718-30.
169. Rosskopf S, Leitner J, Zlabinger GJ, Steinberger P. CTLA-4 antibody ipilimumab negatively affects CD4(+) T-cell responses in vitro. Cancer Immunol Immunother 2019;68:1359-68.
170. Turnis ME, Andrews LP, Vignali DA. Inhibitory receptors as targets for cancer immunotherapy. Eur J Immunol 2015;45:1892-905.
171. Anderson AC. Tim-3: an emerging target in the cancer immunotherapy landscape. Cancer Immunol Res 2014;2:393-8.
172. Huang YH, Zhu C, Kondo Y, Anderson AC, Gandhi A, Russell A, et al. CEACAM1 regulates TIM-3-mediated tolerance and exhaustion. Nature 2015;517:386-90.
173. Joller N, Kuchroo VK. Tim-3, Lag-3, and TIGIT. Curr Top Microbiol Immunol 2017;410:127-56.
174. Zhou G, Sprengers D, Boor PPC, Doukas M, Schutz H, Mancham S, et al. Antibodies Against Immune Checkpoint Molecules Restore Functions of Tumor-Infiltrating T Cells in Hepatocellular Carcinomas. Gastroenterology 2017;153:1107-19 e10.
175. Lozano E, Dominguez-Villar M, Kuchroo V, Hafler DA. The TIGIT/CD226 axis regulates human T cell function. J Immunol 2012;188:3869-75.
176. Attanasio J, Wherry EJ. Costimulatory and Coinhibitory Receptor Pathways in Infectious Disease. Immunity 2016;44:1052-68.
177. Chauvin JM, Pagliano O, Fourcade J, Sun Z, Wang H, Sander C, et al. TIGIT and PD-1 impair tumor antigen-specific CD8(+) T cells in melanoma patients. J Clin Invest 2015;125:2046-58.
178. Zhang Q, Bi J, Zheng X, Chen Y, Wang H, Wu W, et al. Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat Immunol 2018;19:723-32.
179. Yang ZZ, Kim HJ, Wu H, Jalali S, Tang X, Krull JE, et al. TIGIT Expression Is Associated with T-cell Suppression and Exhaustion and Predicts Clinical Outcome and Anti-PD-1 Response in Follicular Lymphoma. Clin Cancer Res 2020;26:5217-31.
180. Ostroumov D, Duong S, Wingerath J, Woller N, Manns MP, Timrott K, et al. Transcriptome profiling identifies TIGIT as a marker of T cell exhaustion in liver cancer. Hepatology 2021;73:1399-418.
181. Minnie SA, Kuns RD, Gartlan KH, Zhang P, Wilkinson AN, Samson L, et al. Myeloma escape after stem cell transplantation is a consequence of T-cell exhaustion and is prevented by TIGIT blockade. Blood 2018;132:1675-88.
182. Johnson MO, Siska PJ, Contreras DC, Rathmell JC. Nutrients and the microenvironment to feed a T cell army. Semin Immunol 2016;28:505-13.
183. Jones RG, Thompson CB. Revving the engine: signal transduction fuels T cell activation. Immunity 2007;27:173-8.
184. Chang CH, Curtis JD, Maggi LB, Jr., Faubert B, Villarino AV, O'Sullivan D, et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 2013;153:1239-51.
185. Pearce EL, Pearce EJ. Metabolic pathways in immune cell activation and quiescence. Immunity 2013;38:633-43.
186. O'Sullivan D, van der Windt GJ, Huang SC, Curtis JD, Chang CH, Buck MD, et al. Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity 2014;41:75-88.
187. van der Windt GJ, Everts B, Chang CH, Curtis JD, Freitas TC, Amiel E, et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 2012;36:68-78.
188. Geiger R, Rieckmann JC, Wolf T, Basso C, Feng Y, Fuhrer T, et al. L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity. Cell 2016;167:829-42 e13.
189. Nakaya M, Xiao Y, Zhou X, Chang JH, Chang M, Cheng X, et al. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity 2014;40:692-705.
190. Doedens AL, Phan AT, Stradner MH, Fujimoto JK, Nguyen JV, Yang E, et al. Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen. Nat Immunol 2013;14:1173-82.
191. Ho PC, Bihuniak JD, Macintyre AN, Staron M, Liu X, Amezquita R, et al. Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses. Cell 2015;162:1217-28.
192. Mineharu Y, Kamran N, Lowenstein PR, Castro MG. Blockade of mTOR signaling via rapamycin combined with immunotherapy augments antiglioma cytotoxic and memory T-cell functions. Mol Cancer Ther 2014;13:3024-36.
193. Agnellini P, Wolint P, Rehr M, Cahenzli J, Karrer U, Oxenius A. Impaired NFAT nuclear translocation results in split exhaustion of virus-specific CD8+ T cell functions during chronic viral infection. Proc Natl Acad Sci U S A 2007;104:4565-70.
194. Intlekofer AM, Takemoto N, Kao C, Banerjee A, Schambach F, Northrop JK, et al. Requirement for T-bet in the aberrant differentiation of unhelped memory CD8+ T cells. J Exp Med 2007;204:2015-21.
195. Kaech SM, Cui W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol 2012;12:749-61.
196. Banerjee A, Gordon SM, Intlekofer AM, Paley MA, Mooney EC, Lindsten T, et al. Cutting edge: The transcription factor eomesodermin enables CD8+ T cells to compete for the memory cell niche. J Immunol 2010;185:4988-92.
197. Macian F, Garcia-Rodriguez C, Rao A. Gene expression elicited by NFAT in the presence or absence of cooperative recruitment of Fos and Jun. EMBO J 2000;19:4783-95.
198. Martinez GJ, Pereira RM, Aijo T, Kim EY, Marangoni F, Pipkin ME, et al. The transcription factor NFAT promotes exhaustion of activated CD8(+) T cells. Immunity 2015;42:265-78.
199. Man K, Gabriel SS, Liao Y, Gloury R, Preston S, Henstridge DC, et al. Transcription Factor IRF4 Promotes CD8(+) T Cell Exhaustion and Limits the Development of Memory-like T Cells during Chronic Infection. Immunity 2017;47:1129-41 e5.
200. McKinney EF, Lee JC, Jayne DR, Lyons PA, Smith KG. T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. Nature 2015;523:612-6.
201. Long SA, Thorpe J, DeBerg HA, Gersuk V, Eddy J, Harris KM, et al. Partial exhaustion of CD8 T cells and clinical response to teplizumab in new-onset type 1 diabetes. Sci Immunol 2016;1:eaai7793.
202. Williams RL, Cooley S, Bachanova V, Blazar BR, Weisdorf DJ, Miller JS, et al. Recipient T Cell Exhaustion and Successful Adoptive Transfer of Haploidentical Natural Killer Cells. Biol Blood Marrow Transplant 2018;24:618-22.
203. Sarraj B, Ye J, Akl AI, Chen G, Wang JJ, Zhang Z, et al. Impaired selectin-dependent leukocyte recruitment induces T-cell exhaustion and prevents chronic allograft vasculopathy and rejection. Proc Natl Acad Sci U S A 2014;111:12145-50.
204. Bohne F, Londono MC, Benitez C, Miquel R, Martinez-Llordella M, Russo C, et al. HCV-induced immune responses influence the development of operational tolerance after liver transplantation in humans. Sci Transl Med 2014;6:242ra81.
205. Fribourg M, Anderson L, Fischman C, Cantarelli C, Perin L, La Manna G, et al. T-cell exhaustion correlates with improved outcomes in kidney transplant recipients. Kidney Int 2019;96:436-49.
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Issue | Vol 61 No 2 (2023) | |
Section | Review Article(s) | |
DOI | https://doi.org/10.18502/acta.v61i2.12530 | |
Keywords | ||
T cell exhaustion NK cell B cell Chronic infection Cancer Immune checkpoint |
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