Early T follicular helper cell activity accelerates hepatitis C virus-specific B cell expansion.
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.
['Salinas|Eduardo|E|', 'Boisvert|Maude|M|', 'Upadhyay|Amit A|AA|', 'Bédard|Nathalie|N|', 'Nelson|Sydney A|SA|', 'Bruneau|Julie|J|', 'Derdeyn|Cynthia A|CA|', 'Marcotrigiano|Joseph|J|', 'Evans|Matthew J|MJ|', 'Bosinger|Steven E|SE|', 'Shoukry|Naglaa H|NH|', 'Grakoui|Arash|A|']
D000208:Acute Disease D001402:B-Lymphocytes D045744:Cell Line, Tumor D049109:Cell Proliferation D005260:Female D019698:Hepatitis C, Chronic D006801:Humans D008297:Male D000081246:RNA-Seq D059010:Single-Cell Analysis D006377:T-Lymphocytes, Helper-Inducer
Hepatitis B cells Adaptive immunity Immunology Infectious disease