Early T follicular helper cell activity accelerates hepatitis C virus-specific B cell expansion
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
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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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 4

VH1-69 usage is higher in BCR repertoire of E2-specific MBCs from chronically infected subjects compared with BCR of resolvers.

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VH1-69 usage is higher in BCR repertoire of E2-specific MBCs from chroni...
(A–C) Circos diagrams showing relative frequencies of V gene pairs from heavy and light chains of pooled E2-specific MBCs from resolvers (SR, n = 6 subjects, 219 pooled cells, A) at late acute stage and chronically infected (CI) subjects (n = 5) at late acute (123 pooled cells, B) and follow-up (403 pooled cells, C) time points. The width of each ribbon indicates the frequency of the VH–VK/VL pairing. The length of the arc corresponds to V gene frequency. (D and E) Relative abundances of heavy (D) or light (E) chain V genes in BCRs of pooled E2-specific MBCs from resolvers (dark gray) at late acute and CI subjects at late acute (white, red border) or follow-up (solid red) time points, presented as mean percentages of repertoire ± SD. Two-way ANOVA with Bonferroni’s post hoc test (D and E), unpaired, Mann-Whitney U test (F). *P < 0.05; **P < 0.01; ***P < 0.001; NS, P > 0.05.