Chronic infection perturbs the affinity hierarchy of antiviral B cells
Abstract
A key function of the germinal center (GC) reaction consists in the preferential expansion and enrichment of high-affinity B cell clones. Whether and how persistent viral infection thwarts this purpose remains ill-defined. Here, we transferred monoclonal lymphocytic choriomeningitis virus–specific B cells into persistently infected hosts. High-affinity B cells expanded vigorously, forming GCs and abundant antibody-secreting cells. When failing to clear viremia or to drive viral mutational escape, the expanded B cell population contracted, ending in its quasi-complete disappearance from the spleen, a process we termed “attrition.” In stark contrast, low-affinity B cells expanded and persisted irrespective of high viral loads. B cell attrition was associated with phenotypic and transcriptional alterations including a prominent Blimp-1 transcriptional signature in high-affinity GC B cells. Blimp-1-deficient B cells were resistant to attrition, suggesting a B cell–intrinsic process. Moreover, exogenously supplied antibody feedback prevented attrition, suggesting that the latter may have resulted from excessive antigenic stimulation. Our findings suggest that in chronic viral infection, the incessant exposure to overwhelming amounts of antigen perturbs B cell affinity hierarchies by preferentially dysregulating high-affinity B cells.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (18)
Mirela Dimitrova
Department of Biomedicine, Division of Experimental Virology, University of Basel
Tiago Abreu-Mota
Department of Biomedicine, Division of Experimental Virology, University of Basel
Jonas Fixemer
Department of Biomedicine, Division of Experimental Virology, University of Basel
Weldy V. Bonilla
Department of Biomedicine, Division of Experimental Virology, University of Basel
Anna-Friederike Marx
Department of Biomedicine, Division of Experimental Virology, University of Basel
Min Lu
College of Chemistry and Chemical Engineering, Frontiers Science Center for Rare Isotopes
Karen Tintignac
Department of Biomedicine, Division of Experimental Virology, University of Basel
Anna Lena Kastner
Department of Biomedicine, Division of Experimental Virology, University of Basel
Yusuf I. Ertuna
Department of Biomedicine, Division of Experimental Virology, University of Basel
Marianna Florova
Department of Biomedicine, Division of Experimental Virology, University of Basel
Matias Ciancaglini
Department of Biomedicine, Division of Experimental Virology, University of Basel
Kerstin Narr
Department of Biomedicine, Division of Experimental Virology, University of Basel
Karsten Stauffer
Department of Biomedicine, Division of Experimental Virology, University of Basel
Julien Roux
Department of Biomedicine, Bioinformatics Core Facility, University Hospital Basel
Philippe Demougin
Genomics Facility Basel, Pharmacenter, University of Basel
Ingrid Wagner
Department of Pathology and Immunology, University of Geneva
Doron Merkler
Department of Pathology and Immunology, Faculty of Medicine, University of Geneva
Daniel D. Pinschewer
Department of Biomedicine, Division of Experimental Virology, University of Basel