Early T follicular helper cell activity accelerates hepatitis C virus-specific B cell expansion
Eduardo Salinas, … , Naglaa H. Shoukry, Arash Grakoui
Eduardo Salinas, … , Naglaa H. Shoukry, Arash Grakoui
Published January 19, 2021
Citation Information: J Clin Invest. 2021;131(2):e140590. https://doi.org/10.1172/JCI140590.
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Research Article Immunology Infectious disease

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

Abstract

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.

Authors

Eduardo Salinas, Maude Boisvert, Amit A. Upadhyay, Nathalie Bédard, Sydney A. Nelson, Julie Bruneau, Cynthia A. Derdeyn, Joseph Marcotrigiano, Matthew J. Evans, Steven E. Bosinger, Naglaa H. Shoukry, Arash Grakoui

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Figure 1

HCV-specific antibodies in the plasma of chronically infected subjects are more abundant and react to a wider breadth of HCV genotypes than antibodies in plasma from resolvers.

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HCV-specific antibodies in the plasma of chronically infected subjects a...
(A and B) Longitudinal anti-E2 and NS3 IgG responses in plasma measured by ELISA and represented as OD450–570 with subtraction of the baseline sample for each subject (baseline > 8 weeks before EDI; early acute, 8 ± 2 weeks after EDI; late acute, 20 ± 4 weeks after EDI; follow-up, > 51 weeks after EDI). Antigens are indicated on top of the graphs. Each symbol represents a single subject. (A) Resolvers (black, n = 8). (B) Chronically infected subjects (red, n = 10). (C) Combined data from A and B, presented as mean ± SD for each group. (D) Heatmaps showing the magnitude of the ELISA response at follow-up against different E2 and NS3 proteins. Infecting HCV genotype for each subject is indicated on the left. Key: blue, low or no response; yellow, medium response; red, maximum response. (E and F) Anti-rubella virus IgG response (E) and HBsAg (F) for resolvers (SR, n = 8) and chronically infected subjects (CI, n = 10). Values for healthy donor group (n = 10) were only available for HBsAg (gray). (C, E, and F) Data are shown as means for each group of subjects and error bars represent SD. Two-way repeated measure ANOVA with Tukey’s post hoc test. *P < 0.05; **P < 0.01; ***P < 0.001; NS, P > 0.05.