RT Journal Article
SR Electronic
T1 Chronic viral infection promotes early germinal center exit of B cells and impaired antibody development
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 849844
DO 10.1101/849844
A1 Ryan P. Staupe
A1 Laura A. Vella
A1 Sasikanth Manne
A1 Josephine R. Giles
A1 Wenzhao Meng
A1 Ramin Sedaghat Herati
A1 Omar Khan
A1 Jennifer E. Wu
A1 Amy E. Baxter
A1 Eline T. Luning Prak
A1 E. John Wherry
YR 2019
UL http://biorxiv.org/content/early/2019/11/21/849844.abstract
AB 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.