Long-primed germinal centres with enduring affinity maturation and clonal migration

Article

关键词: NEUTRALIZING ANTIBODY-RESPONSES;    NONHUMAN-PRIMATES;    HIV;    CELLS;    DYNAMICS;   

DOI  :  10.1038/s41586-022-05216-9

来源: SCIE

【 摘 要 】

Germinal centres are the engines of antibody evolution. Here, using human immunodeficiency virus (HIV) Env protein immunogen priming in rhesus monkeys followed by a long period without further immunization, we demonstrate germinal centre B (B-GC) cells that last for at least 6 months. A 186-fold increase in B-GC cells was present by week 10 compared with conventional immunization. Single-cell transcriptional profiling showed that both light- and dark-zone germinal centre states were sustained. Antibody somatic hypermutation of B-GC cells continued to accumulate throughout the 29-week priming period, with evidence of selective pressure. Env-binding B-GC cells were still 49-fold above baseline at 29 weeks, which suggests that they could remain active for even longer periods of time. High titres of HIV-neutralizing antibodies were generated after a single booster immunization. Fully glycosylated HIV trimer protein is a complex antigen, posing considerable immunodominance challenges for B cells(1,2). Memory B cells generated under these long priming conditions had higher levels of antibody somatic hypermutation, and both memory B cells and antibodies were more likely to recognize non-immunodominant epitopes. Numerous B-GC cell lineage phylogenies spanning more than the 6-month germinal centre period were identified, demonstrating continuous germinal centre activity and selection for at least 191 days with no further antigen exposure. A long-prime, slow-delivery (12 days) immunization approach holds promise for difficult vaccine targets and suggests that patience can have great value for tuning of germinal centres to maximize antibody responses.

【 授权许可】

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