T Follicular Helper Cells Improve Chronic Hepatitis B Patient Response to Interferon by Promoting B Cell Differentiation and HBsAb Production

Abstract

Background: Hepatitis B surface antigen (HBsAg) seroconversion is considered the best outcome in 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 of patients with chronic hepatitis B (CHB). Methods: We first examined the significance of circulating T follicular helper (TFH) cells in the therapeutic response to PEG-IFN-α in patients with CHB. Flow cytometry was used to analyze the circulating TFH cells from 15 healthy individuals and 42 patients with CHB who exhibited 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. In addition, the capacity of different TFH subsets to activate B cells and stimulate IgG production was examined using co-culture experiments. Findings: Longitudinal analysis revealed specific and significant increases in CD40L+CD4+ CXCR5+ TFH cells in CRG patients compared with NRG and ICRG patients given PEG-IFN-α monotherapy. In vitro co-culture experiments demonstrated that blocking CD40-CD40L signaling, but not ICOS-ICOSL signaling, specifically inhibited B cell activation and IgG production. In addition, HBV may impair the TFH function by boosting inhibitory regulatory T cells. Transcriptome analysis further revealed the upregulation of CD40L, but not ICOS, in TFH cells isolated from CRG patients. Interpretation: TFH cells, particularly those associated with CD40L expression, stimulate B cell differentiation and improve HBsAg seroconversion in patients with CHB following PEG-IFN-α treatment. Funding Statement: This research was funded by the National Natural Science Foundation of China (nos. 30972610, 81273240, 91742107, 81570002), National Key Research and Development Program (nos. 2017YFC0910000, 2017YFD0501300), Jilin Province Science and Technology Agency (nos. 20190101022JH, 2019J026, 20170622009JC, 2017C021, 2017J039, SXGJXX2017-8, JJKH20180197KJ, DBXM154-2018, 2018SCZWSZX-015), and the Fund of the State Key Laboratory of Kidney Diseases in PLA General Hospital (nos.KF-01-147). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The design of this study followed the guidelines of the Declaration of Helsinki and was approved by the Human Ethics Committee of the First Hospital of Jilin University (Changchun, Jilin, China). Written informed consent was obtained from all participants.