Chronic Infection Perturbs the Affinity Hierarchy of Antiviral B Cells
The germinal center (GC) subjects antigen-specific B cells to a Darwinian selection process. Whether and how persistent viral infection perturbs the intended affinity hierarchy 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 gain the upper hand over the virus, the expanded B cell population contracted, ending in its quasi-complete disappearance, a process 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, indicating the latter resulted from excessive stimulation. Our findings reveal that in chronic viral infection the incessant activation by overwhelming amounts of antigen perturbs B cell affinity hierarchies by preferentially dysregulating high-affinity B cells.