Early T follicular helper cell activity accelerates hepatitis C virus-specific B cell expansion
Autor: | Cynthia A. Derdeyn, Eduardo Salinas, Joseph Marcotrigiano, Julie Bruneau, Nathalie Bédard, Naglaa H. Shoukry, Steven E. Bosinger, Matthew J. Evans, Amit A. Upadhyay, Arash Grakoui, Sydney A. Nelson, Maude Boisvert |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Male medicine.drug_class Hepatitis C virus medicine.disease_cause Monoclonal antibody Virus 03 medical and health sciences Interleukin 21 0302 clinical medicine Cell Line Tumor medicine Humans RNA-Seq Memory B cell B cell Cell Proliferation B-Lymphocytes biology business.industry General Medicine T-Lymphocytes Helper-Inducer Hepatitis C Chronic 3. Good health Chronic infection 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Immunology Acute Disease biology.protein Female Antibody Single-Cell Analysis business Research Article |
Zdroj: | J Clin Invest |
ISSN: | 1558-8238 |
Popis: | 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. |
Databáze: | OpenAIRE |
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