Acknowledgement
This study was supported by the Research and Development Planned Project in Key Areas of Guangdong Province (grant No. 2019B110233002), the Guangdong Basic and Applied Basic Research Foundation (No. 2020A1515010052), the Guangzhou Science and Technology Project (grant No. 202002030431), and the Joint Key Projects of City and Hospital of Guangzhou Science and Technology (grant No. 202201020422).
References
- Revill PA, Chisari FV, Block JM, Dandri M, Gehring AJ, Guo H, et al. A global scientific strategy to cure hepatitis B. Lancet Gastroenterol Hepatol 2019;4:545–58. https://doi.org/10.1016/S2468-1253(19)30119-0
- Bertoletti A and Wang FS. Overview of the special issue on HBV immunity. Cell Mol Immunol 2015;12:253–4. https://doi.org/10.1038/cmi.2015.24
- Bertoletti A and Ferrari C. Adaptive immunity in HBV infection. J Hepatol 2016;64(S):S71–83. https://doi.org/10.1016/j.jhep.2016.01.026
- Sancho D, Gómez M, Sánchez-Madrid F. CD69 is an immunoregulatory molecule induced following activation. Trends Immunol 2005;26:136–40. https://doi.org/10.1016/j.it.2004.12.006
- Hamann J, Fiebig H, Strauss M. Expression cloning of the early activation antigen CD69, a type II integral membrane protein with a C-type lectin domain. J Immunol 1993;150:4920–7. https://doi.org/10.4049/jimmunol.150.11.4920
- Testi R, D'Ambrosio D, De Maria R, Santoni A. The CD69 receptor: a multipurpose cell-surface trigger for hematopoietic cells. Immunol Today 1994;15:479–83. https://doi.org/10.1016/0167-5699(94)90193-7
- Moretta A, Poggi A, Pende D, Tripodi G, Orengo AM, Pella N, et al. CD69- mediated pathway of lymphocyte activation: anti-CD69 monoclonal antibodies trigger the cytolytic activity of different lymphoid effector cells with the exception of cytolytic T lymphocytes expressing T cell receptor alpha/beta. J Exp Med 1991;174:1393–8. https://doi.org/10.1084/jem.174.6.1393
- Borrego F, Robertson MJ, Ritz J, Peña J, Solana R. CD69 is a stimulatory receptor for natural killer cell and its cytotoxic effect is blocked by CD94 inhibitory receptor. Immunology 1999;97:159–65. https://doi.org/10.1046/j.1365-2567.1999.00738.x
- Cebrián M, Yagüe E, Rincón M, López-Botet M, de Landázuri MO, Sánchez-Madrid F. Triggering of T cell proliferation through AIM, an activation inducer molecule expressed on activated human lymphocytes. J Exp Med 1988;168:1621–37. https://doi.org/10.1084/jem.168.5.1621
- Testi R, Phillips JH, Lanier LL. T cell activation via Leu-23 (CD69). J Immunol 1989;143:1123–8. https://doi.org/10.4049/jimmunol.143.4.1123
- de la Fuente H, Cruz-Adalia A, Martinez Del Hoyo G, Cibrián-Vera D, Bonay P, Pérez-Hernández D, et al. The leukocyte activation receptor CD69 controls T cell differentiation through its interaction with galec-tin-1. Mol Cell Biol 2014;34:2479–87. https://doi.org/10.1128/MCB.00348-14
- Martín P, Gómez M, Lamana A, Cruz-Adalia A, Ramírez-Huesca M, Ursa MA, et al. CD69 association with Jak3/Stat5 proteins regulates Th17 cell differentiation. Mol Cell Biol 2010;30:4877–89. https://doi.org/10.1128/MCB.00456-10
- Das A, Hoare M, Davies N, Lopes AR, Dunn C, Kennedy PTF, et al. Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection. J Exp Med 2008;205:2111–24. https://doi.org/10.1084/jem.20072076
- Fletcher SP, Chin DJ, Ji Y, Iniguez AL, Taillon B, Swinney DC, et al. Transcriptomic analysis of the woodchuck model of chronic hepatitis B. Hepatology 2012;56:820–30. https://doi.org/10.1002/hep.25730
- Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018;67:1560–99. https://doi.org/10.1002/hep.29800
- Gu Y, Li X, Gu L, Lian Y, Wang K, Chen Y, et al. An immuno-clinic score model for evaluating T cell immunity and predicting early antiviral therapy effectiveness in chronic hepatitis B. Aging (Albany, NY) 2020;12: 26063–79. https://doi.org/10.18632/aging.202274
- Freeman BE, Hammarlund E, Raué HP, Slifka MK. Regulation of innate CD8+ T-cell activation mediated by cytokines. Proc Natl Acad Sci U S A 2012;109:9971–6. https://doi.org/10.1073/pnas.1203543109
- Sallusto F, Lenig D, Förster R, Lipp M, and Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 1999;401:708–12. https://doi.org/10.1038/44385
- Li L, Yang B, Zhang X, Lao S, Changyou W. Mycobacterium tuberculosisspecific polyfunctional cytotoxic CD8+ T cells express CD69. Tuberc (Edinb) 2014;94:219–25. https://doi.org/10.1016/j.tube.2013.12.007
- Martín P, Gómez M, Lamana A, Matesanz Marín A, Cortés JR, RamírezHuesca M, et al. The leukocyte activation antigen CD69 limits allergic asthma and skin contact hypersensitivity. J Allergy Clin Immunol 2010; 126:355–65, 65 e1–3. https://doi.org/10.1016/j.jaci.2010.05.010
- Cruz-Adalia A, Jiménez-Borreguero LJ, Ramírez-Huesca M, Chico-Calero I, Barreiro O, López-Conesa E, et al. CD69 limits the severity of cardiomyopathy after autoimmune myocarditis. Circulation 2010;122:1396–404. https://doi.org/10.1161/CIRCULATIONAHA.110.952820
- Shiow LR, Rosen DB, Brdicková N, Xu Y, An J, Lanier LL, et al. CD69 acts downstream of interferon-alpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature 2006;440:540–4. https://doi.org/10.1038/nature04606
- Jiménez-Fernández M, Rodríguez-Sinovas C, Cañes L, Ballester-Servera C, Vara A, Requena S, et al. CD69-oxLDL ligand engagement induces programmed cell death 1 (PD-1) expression in human CD4+T lymphocytes. Cell Mol Life Sci 2022;79:468. https://doi.org/10.1007/s00018-022-04481-1
- Gu Y, Lian Y, Gu L, Chen L, Li X, Zhou L, et al. Correlations between cytokines produced by T cells and clinical-virological characteristics in untreated chronic hepatitis B patients. BMC Infect Dis 2019;19:216. https://doi.org/10.1186/s12879-019-3853-2
- Khanam A, Chua JV, Kottilil S. Immunopathology of chronic hepatitis B infection: role of innate and adaptive immune response in disease progression. Int J Mol Sci 2021;22:5497. https://doi.org/10.3390/ijms22115497
- Cibrián D and Sánchez-Madrid F. CD69: from activation marker to metabolic gatekeeper. Eur J Immunol 2017;47:946–53. https://doi.org/10.1002/eji.201646837
- Yu L, Zhou B, Zhu Y, Li L, Zhong Y, Zhu L, et al. HSF1 promotes CD69+ Treg differentiation to inhibit colitis progression. Theranostics 2023;13: 1892–905. https://doi.org/10.7150/thno.78078
- Yang FA-OX, Yu XA-O, Zhou C, Mao R, Zhu M, Zhu H, et al. Hepatitis B e antigen induces the expansion of monocytic myeloid-derived suppressor cells to dampen T-cell function in chronic hepatitis B virus infection. PLoS Pathog 2019;15:e1007690. https://doi.org/10.1371/journal.ppat.1007690
- Tang R, Lei Z, Wang X, Qi Q, He J, Liu D, et al. Hepatitis B envelope antigen increases Tregs by converting CD4+ CD25– T cells into CD4+CD25+Foxp3+ Tregs. Exp Ther Med 2020;20:3679–86. https://doi.org/10.3892/etm.2020.9107
- Chen LM, Fan XG, Ma J, He B, and Jiang YF. Molecular mechanisms of HBeAg in persistent HBV infection. Hepatol Int 2017;11:79–86. https://doi.org/10.1007/s12072-016-9734-5
- Ma Q, Dong X, Liu S, Zhong T, Sun D, Zong L, et al. Hepatitis B e antigen induces NKG2A+ natural killer cell dysfunction via regulatory T cell-derived interleukin 10. In: Chronic hepatitis B virus infection. Front Cell Dev Biol 2020;8:421. https://doi.org/10.3389/fcell.2020.00421
- Datar I, Sanmamed MF, Wang J, Henick BS, Choi J, Badri T, et al. Expression analysis and significance of PD-1, LAG-3, and TIM-3 in human nonsmall cell lung cancer using spatially resolved and multiparametric single-cell analysis. Clin Cancer Res 2019;25:4663–73. https://doi.org/10.1158/1078-0432.CCR-18-4142
- Huang W, He W, Shi X, Ye Q, He X, Dou L, et al. Mucosal-associated invariant T-cells are severely reduced and exhausted in humans with chronic HBV infection. J Viral Hepat 2020;27:1096–107. https://doi.org/10.1111/jvh.13341
- Cortés JR, Sánchez-Díaz R, Bovolenta ER, Barreiro O, Lasarte S, Matesanz-Marín A, et al. Maintenance of immune tolerance by Foxp3+ regulatory T cells requires CD69 expression. J Autoimmun 2014;55:51–62. https://doi.org/10.1016/j.jaut.2014.05.007
- Hossen MM, Ma Y, Yin Z, Xia Y, Du J, Huang JY, et al. Current understanding of CTLA-4: from mechanism to autoimmune diseases. Front Immunol 2023;14:1198365. https://doi.org/10.3389/fimmu.2023.1198365
- Walker LSK. Treg and CTLA-4: two intertwining pathways to immune tolerance. J Autoimmun 2013;45:49–57. https://doi.org/10.1016/j.jaut.2013.06.006
- Goronzy JJ and Weyand CM. Understanding immunosenescence to improve responses to vaccines. Nat Immunol 2013;14:428–36. https://doi.org/10.1038/ni.2588
- Wherry EJ and Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol 2015;15:486–99. https://doi.org/10.1038/nri3862