Longitudinal characterization of phenotypic profile of T cells in chronic hepatitis B identifies immune markers associated with HBsAg loss
Shue Xiong,
Dan Zhu,
Boyun Liang,
Mingyue Li,
Wen Pan,
Junyi He,
Hua Wang,
Kathrin Sutter,
Ulf Dittmer,
Mengji Lu,
Di Liu,
Dongliang Yang,
Jia Liu,
Xin Zheng
Affiliations
Shue Xiong
Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
Dan Zhu
Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
Boyun Liang
Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
Mingyue Li
Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
Wen Pan
Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
Junyi He
Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
Hua Wang
Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
Kathrin Sutter
Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen 45147, Germany; Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
Ulf Dittmer
Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen 45147, Germany; Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
Mengji Lu
Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen 45147, Germany; Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
Di Liu
Pritzker School of Medicine, University of Chicago, Chicago, USA
Dongliang Yang
Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
Jia Liu
Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
Xin Zheng
Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
Background: The current desirable endpoint of treatment against chronic hepatitis B virus infection (cHBV) is to achieve a functional cure, which is defined as HBsAg loss (sAg-L) with or without anti-HBs seroconversion. However, the immunological features that are associated with functional cure have not been studied in detail. Methods: 172 cHBV patients (67 HBeAg+ and 105 HBeAg-), including 141 HBsAg retained (sAg-R) patients (115 chronic hepatitis and 26 asymptomatic carriers), 31 sAg-L patients, and 24 healthy individuals (vaccinated but not infected with HBV) were examined for their T cell phenotypic profile and HBV-specific T cell responses by flow cytometry. 18 cHBV patients with low serum HBsAg levels were also longitudinally followed for their T cell phenotypic profile and HBV-specific T cell responses up to 60 weeks. Findings: sAg-L patients showed distinct CD4+ and CD8+ T cell phenotype fingerprints compared to those of sAg-R patients, as mainly indicated by the upregulation of HLA-DR on both CD4+ and CD8+ T cells, and a potent HBcAg-specific CD8+ T cell response. The changes in the T cell phenotype in cHBV patients were even more profound during rapid HBsAg decrease and was associated with interferon α treatment. The expression of HLA-DR (r = 0·3269, p = 0·0037), CD95 (r = 0·2796, p = 0·0151), CD40L (r = 0·2747, p = 0·0156), CTLA-4 (r = 0·2786, p = 0·0148), TIM-3 (r = 0·3082, p = 0·0068), CD107a (r = 0·3597, p = 0·0013) on CD4+ T cells, and HLA-DR (r = 0·3542, p = 0·0016), CD69 (r = 0·2507, p = 0·0279), CD107a (r = 0·2875, p = 0·0112) on CD8+ T cells were positively correlated with the rate of HBsAg decrease. The expression of HLA-DR (r = 0·2846, p = 0·0009) and CD95 (r = 0·2442, p = 0·0049) on CD8+ T cells were positively correlated with the magnitude of the HBcAg-specific T cell responses in cHBV patients. Importantly, CTLA-4, CD95 and CD107a expression on CD4+ T cells, as well as HLA-DR and TIM-3 expression on CD8+ T cells in combination with HBsAg quantification were identified as potential predictive factors for sAg-L within 48 weeks in cHBV patients. Interpretation: The onset of HBsAg decrease and subsequent loss in cHBV patients on treatment is associated with significant alterations of both CD4+ and CD8+ T cell phenotypes. Characterization of the T cell phenotype in cHBV patients may present predicative value for sAg-L. Funding: National Natural Science Foundation of China, National Scientific and Technological Major Project of China, Integrated Innovative Team for Major Human Diseases Program of Tongji Medical College, “Double-First Class” Project for the International Cooperation Center on Infection and Immunity, HUST.
