Chronic viral infection promotes early germinal center exit of B cells and impaired antibody development.
Ryan P Staupe,
Laura A. Vella,
Josephine R. Giles,
Ramin Sedaghat Herati,
Jennifer E Wu,
Amy E. Baxter,
Eline T Luning Prak,
E John Wherry
Posted 21 Nov 2019
bioRxiv DOI: 10.1101/849844
Posted 21 Nov 2019
Chronic viral infections disrupt B cell responses leading to impaired affinity maturation and delayed control of viremia. Previous studies have identified early pre-germinal center (GC) B cell attrition but the impact of chronic infections on B cell fate decisions in the GC remains poorly understood. To address this question, we used single-cell transcriptional profiling of virus-specific GC B cells to test the hypothesis that chronic viral infection disrupted GC B cell fate decisions leading to suboptimal humoral immunity. These studies revealed a critical GC differentiation checkpoint that is disrupted by chronic infection, specifically at the point of dark zone re-entry. During chronic viral infection, virus-specific GC B cells were shunted towards terminal plasma cell (PC) or memory B cell (MBC) fates at the expense of continued participation in the GC. Early GC exit was associated with decreased B cell mutational burden and antibody quality. Persisting antigen and inflammation independently drove facets of dysregulation, with a key role for inflammation in directing premature terminal GC B cell differentiation and GC exit. Thus, these studies define GC defects during chronic viral infection and identify a critical GC checkpoint that is short-circuited, preventing optimal maturation of humoral immunity.
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