Yong Liu1, Xintong Hu1, Xiaoli Hu2, Lei Yu3, Huifan Ji4, Wanyu Li4, Yanjun Cai4, Genhong Cheng1,5, Yanfang Jiang6,7. 1. Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun, 130021, China. 2. Department of Infectious Disease, Heilongjiang Provincial Hospital, Harbin, China. 3. Department of Infectious Disease, The Fourth Hospital of Harbin Medical University, Harbin, China. 4. Department of Hepatology, The First Hospital of Jilin University, Changchun, China. 5. Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, 90095, USA. 6. Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun, 130021, China. yanfangjiang@hotmail.com. 7. Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, 130021, China. yanfangjiang@hotmail.com.
Abstract
BACKGROUND AND AIMS: Hepatitis B surface antigen (HBsAg) seroconversion is considered the optimal outcome of the treatment of chronic hepatitis B virus (HBV) infection. In this study, we aimed to determine the cellular and molecular mechanisms by which pegylated interferon alpha (PEG-IFN-α) improves the seroconversion rate in patients with chronic hepatitis B (CHB). METHODS: Flow cytometry was performed using circulating T follicular helper (TFH) cells from 15 healthy individuals and 45 patients with CHB presenting different treatment responses [complete response group (CRG), incomplete response group (ICRG), and nonresponse group (NRG)] to the standard 48-week regimen of PEG-IFN-α monotherapy to examine the significance of circulating TFH cells in the therapeutic response of patients with CHB to PEG-IFN-α. In addition, the capacities of different TFH subsets to activate B cells and stimulate IgG production were assessed by performing coculture experiments. RESULTS: Longitudinal analysis revealed specific and significant increases in the numbers of CD40L+CD4+CXCR5+ TFH cells in the CRG compared with the NRG and ICRG. According to the results of in vitro coculture experiments, blocking CD40-CD40L signaling, but not ICOS-ICOSL signaling, specifically inhibits B-cell activation and IgG production. HBV may impair TFH cell function by enhancing inhibitory regulatory T-cell activity. Transcriptome analysis further revealed the upregulation of CD40L, but not of ICOS, in TFH cells isolated from the CRG. CONCLUSIONS: TFH cells, particularly those with CD40L expression, stimulate B-cell differentiation and improve the HBsAg seroconversion rate in patients with CHB treated with PEG-IFN-α monotherapy.
BACKGROUND AND AIMS: Hepatitis B surface antigen (HBsAg) seroconversion is considered the optimal outcome of the treatment of chronic hepatitis B virus (HBV) infection. In this study, we aimed to determine the cellular and molecular mechanisms by which pegylated interferon alpha (PEG-IFN-α) improves the seroconversion rate in patients with chronic hepatitis B (CHB). METHODS: Flow cytometry was performed using circulating T follicular helper (TFH) cells from 15 healthy individuals and 45 patients with CHB presenting different treatment responses [complete response group (CRG), incomplete response group (ICRG), and nonresponse group (NRG)] to the standard 48-week regimen of PEG-IFN-α monotherapy to examine the significance of circulating TFH cells in the therapeutic response of patients with CHB to PEG-IFN-α. In addition, the capacities of different TFH subsets to activate B cells and stimulate IgG production were assessed by performing coculture experiments. RESULTS: Longitudinal analysis revealed specific and significant increases in the numbers of CD40L+CD4+CXCR5+ TFH cells in the CRG compared with the NRG and ICRG. According to the results of in vitro coculture experiments, blocking CD40-CD40L signaling, but not ICOS-ICOSL signaling, specifically inhibits B-cell activation and IgG production. HBV may impair TFH cell function by enhancing inhibitory regulatory T-cell activity. Transcriptome analysis further revealed the upregulation of CD40L, but not of ICOS, in TFH cells isolated from the CRG. CONCLUSIONS: TFH cells, particularly those with CD40L expression, stimulate B-cell differentiation and improve the HBsAg seroconversion rate in patients with CHB treated with PEG-IFN-α monotherapy.