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T follicular helper cells improve the response of patients with chronic hepatitis B to interferon by promoting HBsAb production

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

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.

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Abbreviations

AHB:

Chronic active hepatitis B

AHC:

Chronic asymptomatic HBV carriers

CBA:

Cytometric bead array

CHB:

Chronic hepatitis B

CRG:

Complete response group

HBV:

Hepatitis B virus

HBsAg:

Hepatitis B surface antigen

HBsAb:

Anti-HBs antibody

HC:

Healthy control

ICRG:

Incomplete response group

NRG:

Nonresponse group

PBMC:

Peripheral blood mononuclear cell

PD-1:

Programmed cell death protein 1

PEG-IFN-α:

Pegylated interferon alpha

TFH:

T follicular helper

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Funding

This research was funded by grants from the National Natural Science Foundation of China (Nos. 30972610, 81273240, 91742107, and 81570002), National Key Research and Development Program (Nos. 2017YFC0910000 and 2017YFD0501300), and Jilin Province Science and Technology Agency (Nos. 20200403084SF, JLSWSRCZX2020-009, 20200901025SF, 20190101022JH, 2019J026, 20170622009JC, 2017C021, 2017J039, SXGJXX2017-8, JJKH20180197KJ, DBXM154-2018, and 2018SCZWSZX-015).

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Author notes

  1. Yong Liu and Xintong Hu equally contributed to this study.

Authors and Affiliations

  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

    Yong Liu, Xintong Hu, Genhong Cheng & Yanfang Jiang

  2. Department of Infectious Disease, Heilongjiang Provincial Hospital, Harbin, China

    Xiaoli Hu

  3. Department of Infectious Disease, The Fourth Hospital of Harbin Medical University, Harbin, China

    Lei Yu

  4. Department of Hepatology, The First Hospital of Jilin University, Changchun, China

    Huifan Ji, Wanyu Li & Yanjun Cai

  5. Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, 90095, USA

    Genhong Cheng

  6. Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, 130021, China

    Yanfang Jiang

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  1. Yong Liu
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  2. Xintong Hu
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  3. Xiaoli Hu
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  4. Lei Yu
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Contributions

YJ and YL designed and performed the experiments, analyzed the data, and wrote the paper. XH analyzed the data. GC wrote the paper. HJ, XH, WL, YC, and LY provided the samples. All the authors commented on the paper. All authors had access to the study data and reviewed and approved the final manuscript.

Corresponding author

Correspondence to Yanfang Jiang.

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Liu, Y., Hu, X., Hu, X. et al. T follicular helper cells improve the response of patients with chronic hepatitis B to interferon by promoting HBsAb production. J Gastroenterol 57, 30–45 (2022). https://doi.org/10.1007/s00535-021-01840-w

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  • DOI: https://doi.org/10.1007/s00535-021-01840-w

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