Early T follicular helper cell activity accelerates hepatitis C virus-specific B cell expansion

J Clin Invest. 2021 Jan 19;131(2):e140590. doi: 10.1172/JCI140590.


Early appearance of neutralizing antibodies during acute hepatitis C virus (HCV) infection is associated with spontaneous viral clearance. However, the longitudinal changes in antigen-specific memory B cell (MBCs) associated with divergent HCV infection outcomes remain undefined. We characterized longitudinal changes in E2 glycoprotein-specific MBCs from subjects who either spontaneously resolved acute HCV infection or progressed to chronic infection, using single-cell RNA-seq and functional assays. HCV-specific antibodies in plasma from chronically infected subjects recognized multiple E2 genotypes, while those from spontaneous resolvers exhibited variable cross-reactivity to heterotypic E2. E2-specific MBCs from spontaneous resolvers peaked early after infection (4-6 months), following expansion of activated circulating T follicular helper cells (cTfh) expressing interleukin 21. In contrast, E2-specific MBCs from chronically infected subjects, enriched in VH1-69, expanded during persistent infection (> 1 year), in the absence of significantly activated cTfh expansion. Early E2-specific MBCs from spontaneous resolvers produced monoclonal antibodies (mAbs) with fewer somatic hypermutations and lower E2 binding but similar neutralization as mAbs from late E2-specific MBCs of chronically infected subjects. These findings indicate that early cTfh activity accelerates expansion of E2-specific MBCs during acute infection, which might contribute to spontaneous clearance of HCV.

Trial registration: ClinicalTrials.gov NCT01436357.

Keywords: Adaptive immunity; B cells; Hepatitis; Immunology; Infectious disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / pathology
  • Cell Line, Tumor
  • Cell Proliferation*
  • Female
  • Hepatitis C, Chronic / immunology*
  • Hepatitis C, Chronic / pathology
  • Humans
  • Male
  • RNA-Seq*
  • Single-Cell Analysis*
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / pathology

Associated data

  • ClinicalTrials.gov/NCT01436357