Analysis on the function of antigen-specific CD8+ T cells before and after antiviral treatment in patients with hepatitis B virus-related cirrhosis

Abstract

Abstract: Objective To investigate the number and function of hepatitis B virus (HBV) antigen-specific T cells in peripheral blood before and after antiviral treatment of HBV-related cirrhosis, and its correlation with clinical prognosis. Methods Forty-six patients were selected by HLA-A2 classification test, the percentages of HBV antigen-specific T cells in the peripheral blood were detected before and after treatment by flow cytometry through the major histocompatibility complex (MHC) -antigenic peptide tetramer staining, the cytokines secreting ability and phenotype of the cells were detected. Results Human leukocyte-associated antigens HLA-A2 expressed by antigen-specific CD8⁺T cells were detected in 22 patients, the level of liver function marker alanine aminotransferase (ALT) after treatment (31.29±18.42) was significantly lower than that before treatment (124.05±29.18), (u = 72, P=0.015), and the HBV DNA negative rate was 100%. The number of antigen-specific CD8⁺T cells after treatment (1.15±0.37)% was significantly higher than that before treatment (0.65±0.25)%, (u = 59, P<0.0001). The percentage of cells which secreted interferon (IFN-γ) after treatment (6.86±2.08)% was significantly higher than that before treatment (3.58±1.26)%, (u = 46, P<0.0001). The percentage of HBV epitope-specific CD8⁺T cells which expressed inhibitory factor PD-1 after treatment (0.43±0.19)% was significantly lower than that before treatment (0.76±0.43)%, (u = 131, P<0.05). The percentage of HBV epitope-specific CD8⁺T cells which expressed active factor CD28 after treatment (1.03±0.45)% was significantly higher than that before treatment (0.56±0.26)%, (u = 100, P=0.0006). Conclusion The function of antigen-specific CD8⁺T cells in the peripheral blood of patients with HBV-related cirrhosis is defected. After antiviral treatment, the number and function of antigen specific CD8+T cells are both improved.

Key words: Hepatitis B virus-related cirrhosis, Antiviral therapy, Function of antigen specific CD8⁺T cell

GAO De-yong, LOU Xiao-li, MA Shuang, ZHANG Kun-lun, LIU Liang-ming, LIU Hong-xiang. Analysis on the function of antigen-specific CD8+ T cells before and after antiviral treatment in patients with hepatitis B virus-related cirrhosis[J]. Chinese Hepatolgy, 2021, 26(11): 1250-1252.

References

[1] Acerbi G, Montali I, Ferrigno GD, et al. Functional reconstitution of HBV-specific CD8 T cells by in?vitro polyphenol treatment in chronic hepatitis B. J Hepatol,2021,74:783-793.
[2] Lin CY, Tsai MC, Huang CT, et al. Liver injury is associated with enhanced regulatory T-cell activity in patients with chronic hepatitis B. J Viral Hepat,2007,14:503-511.
[3] Bertoletti A, Le Bert N. Immunotherapy for chronic hepatitis B Virus Infection. Gut Liver, 2018,12:497-507.
[4] Lim CJ, Lee YH, Pan L, et al. Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma. Gut, 2019,68:916-927.
[5] 中华医学会感染病学分会,中华医学会肝病学分会. 慢性乙型肝炎防治指南(2015年更新版). 临床肝胆病杂志,2015,31:1941-1960.
[6] 高得勇,王迎迎,汪妍妍,等.替比夫定治疗乙型肝炎肝硬化失代偿疗效分析及对肾脏功能的影响.肝脏,2016,21:722-725.
[7] Fisicaro P, Valdatta C, Massari M, et al. Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B. Gastroenterology,2010, 138:682-93, 693.e1-4.
[8] Ye B, Liu X, Li X, et al. T-cell exhaustion in chronic hepatitis B infection: current knowledge and clinical significance. Cell Death Dis,2015,6:e1694.
[9] Kurktschiev PD, Raziorrouh B, Schraut W, et al. Dysfunctional CD8⁺T cells in hepatitis B and C are characterized by a lack of antigen-specific T-bet induction. J Exp Med,2014,211:2047-2059.
[10] 蔡刚,吴蓓颖,范臻佳,沈茜.慢性乙型肝炎患者外周血抗原特异性CD8⁺T细胞功能的初步分析.检验医学,2014,29:10-14.
[11] Nitschke K, Luxenburger H, Kiraithe MM, et al. CD8⁺T-cell responses in hepatitis B and C: the (HLA-) A, B, and C of Hepatitis B and C. Dig Dis,2016,34:396-409.
[12] Cho H, Kang H, Lee HH, et al. Programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) in viral hepatitis. Int J Mol Sci,2017,18:1517.
[13] Gorman JV, Colgan JD. Regulation of T cell responses by the receptor molecule Tim-3. Immunol Res,2014,59:56-65.
[14] Bengsch B, Martin B, Thimme R. Restoration of HBV-specific CD8⁺T cell function by PD-1 blockade in inactive carrier patients is linked to T cell differentiation. J Hepatol,2014, 61:1212-1219.
[15] Ubaldi V, Gatta L, Pace L, et al. CTLA-4 engagement inhibits Th2 but not Th1 cell polarisation. Clin Dev Immunol,2003,10:13-17.
[16] Kato T, Nariuchi H. Polarization of naive CD4⁺T cells toward the Th1 subset by CTLA-4 costimulation. J Immunol,2000,164:3554-3562.
[17] Watanabe T, Bertoletti A, Tanoto TA. PD-1/PD-L1 pathway and T-cell exhaustion in chronic hepatitis virus infection. J Viral Hepat,2010,17:453-458.
[18] Cai H, Liu G, Zhong J, et al. Immune Checkpoints in Viral Infections. Viruses,2020,12:1051.
[19] Li Z, Li N, Zhu Q, et al. Genetic variations of PD1 and TIM3 are differentially and interactively associated with the development of cirrhosis and HCC in patients with chronic HBV infection. Infect Genet Evol, 2013,14:240-246.
[20] Nandi M, Pal S, Ghosh S, et al. CD8⁺CD28^-T cells: key cytotoxic players impacting disease pathogenesis in chronic HBV infection. Clin Sci (Lond),2019,133:1917-1934.
[21] Li X, Kong H, Tian L,et al. Changes of costimulatory molecule CD28 on circulating CD8⁺T cells correlate with disease pathogenesis of chronic hepatitis B. Biomed Res Int, 2014,2014:423181.