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 Article has an altmetric score of 9

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 6

mAbs from resolvers at late acute stage have fewer somatic hypermutation than mAbs from chronically infected subjects at follow-up.

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mAbs from resolvers at late acute stage have fewer somatic hypermutation...
(A–D) SHMs in pooled, single E2-specific MBCs (n = 219) from resolvers (n = 6 subjects, gray violins) and CI subjects (n = 123 cells, n = 5 subjects, white violins with red border) at late acute and CI subjects (n = 5) at follow-up (n = 403 cells, red violins) time points, presented as the number of nucleotide substitutions (A and B) and amino acid mutations (C and D) in heavy (A and C) and light (B and D) chains plotted as absolute number of mutations. (E and F) Correlation between mAbs neutralization combined rank (rank of 1 = best neutralizer, rank of 114 = worst neutralizer, established from H77 and J6/JFH1 neutralization, see Figure 5) and number of SHMs in CDR3H and CDR3L regions of mAbs derived from resolvers (n = 3 subjects, 30 mAbs, E) or chronically infected subjects (n = 3, 30 mAbs, F). (G and H) Number of SHMs in CDR3 regions of all cloned mAbs (G) or the top neutralizers (H, combined rank < 50). (E–H) Each dot represents the rank value for an individual mAb. Results represent means of pooled mAbs and error bars represent SD 1-way ANOVA with Tukey’s post hoc test (A–D) or paired Student’s t test (G and H). *P < 0.05; **P < 0.01; ***P < 0.001; NS, P > 0.05.