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
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.
Trial registration: ClinicalTrials.gov NCT01436357.
Keywords: Adaptive immunity; B cells; Hepatitis; Immunology; Infectious disease.
Conflict of interest statement
Conflict of interest: The authors have declared that no conflict of interest exists.
Figures
![Figure 1. HCV-specific antibodies in the plasma…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7810471/bin/jci-131-140590-g227.jpg)
![Figure 2. Plasma from chronically infected subjects…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7810471/bin/jci-131-140590-g228.jpg)
![Figure 3. E2-specific MBCs undergo earlier expansion…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7810471/bin/jci-131-140590-g229.jpg)
![Figure 4. VH1-69 usage is higher in…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7810471/bin/jci-131-140590-g230.jpg)
![Figure 5. E2-specific mAbs from resolvers neutralize…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7810471/bin/jci-131-140590-g231.jpg)
![Figure 6. mAbs from resolvers at late…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7810471/bin/jci-131-140590-g232.jpg)
![Figure 7. Activated cTfh cells expand early…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7810471/bin/jci-131-140590-g233.jpg)
Source: PubMed