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 7

Activated cTfh cells expand early during acute infection in resolvers but not in chronically infected subjects.

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Activated cTfh cells expand early during acute infection in resolvers bu...
(A) Representative gating strategy of total cTfh cells (CD3+CD4+CD45RA–CXCR5+PD1+FoxP3–), activated cTfh cells (ICOS+), total cTfr cells (CD3+CD4+CD45RA–CXCR5+PD1+FoxP3+), and activated cTfr cells (ICOS+), from PBMCs of HCV-infected subjects. (B) Frequencies of total cTfh cells at different time points in resolvers (n = 10, black) or chronically infected subjects (n = 10, red; see Figure 1). Data from 5 healthy donors (controls) are shown in gray. (C) Frequencies of activated cTfh cells at different time points. (D) Ratio of activated cTfh over cTfr cells at different time points, shown as fold-change from baseline. (E) Frequencies of activated Th1-like (CXCR3+) cTfh cells at different time points. (F) Frequencies of activated Th2-like (CXCR3–) cTfh cells at different time points. (G) Representative gating strategy of cytokine-producing or CD40L-expressing, activated cTfh cells before (no stim, top) and after PMA and ionomycin stimulation (5 hours, bottom). (H–J) Frequencies of ICOS+IL-21+ cells (H), ICOS+CD40L+ cells (I), and ICOS+IFN-γ+ (J) cTfh cells at different time points. (K) Summary heatmaps of the main data from this study. Each component (row) indicates the intensity of response of the indicated test (far left) at the indicated time point (far right). Each square provides data for one resolver (left) or chronically infected subject (right). An X indicates no response (values of 0); N/A, subject for which the test could not be done (no baseline blood sample available). Blue, low or no response; yellow, medium response; red, maximum response. 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.