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

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Long-primed germinal centres with enduring affinity maturation and clonal migration
Nature ( IF 50.5 ) Pub Date : 2022-09-21 , DOI: 10.1038/s41586-022-05216-9
Jeong Hyun Lee _{1,

2,

3} , Henry J Sutton _{1,

2} , Christopher A Cottrell _{2,

3,

4} , Ivy Phung _{1,

2,

5} , Gabriel Ozorowski _{2,

3,

6} , Leigh M Sewall ₆ , Rebecca Nedellec ₄ , Catherine Nakao ₁ , Murillo Silva _{2,

7} , Sara T Richey ₆ , Jonathan L Torres ₆ , Wen-Hsin Lee ₆ , Erik Georgeson _{2,

3,

4} , Michael Kubitz _{2,

3,

4} , Sam Hodges _{2,

3,

4} , Tina-Marie Mullen _{2,

3,

4} , Yumiko Adachi _{2,

3,

4} , Kimberly M Cirelli _{1,

2} , Amitinder Kaur ₈ , Carolina Allers ₈ , Marissa Fahlberg ₈ , Brooke F Grasperge ₈ , Jason P Dufour ₈ , Faith Schiro ₈ , Pyone P Aye ₈ , Oleksandr Kalyuzhniy _{2,

3,

4} , Alessia Liguori _{2,

3,

4} , Diane G Carnathan _{2,

9} , Guido Silvestri _{2,

9} , Xiaoying Shen ₁₀ , David C Montefiori ₁₀ , Ronald S Veazey ₈ , Andrew B Ward _{2,

3,

6} , Lars Hangartner _{2,

4} , Dennis R Burton _{2,

3,

4,

11} , Darrell J Irvine _{2,

7,

11,

12,

13,

14} , William R Schief _{2,

3,

4,

11} , Shane Crotty _{1,

2,

5}

Affiliation

Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA, USA.
Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA, USA.
IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, USA.
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.
Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego, La Jolla, CA, USA.
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
Tulane National Primate Research Center, Tulane School of Medicine, Covington, LA, USA.
Emory National Primate Research Center and Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.
Department of Surgery, Laboratory for AIDS Vaccine Research & Development, Duke University Medical Center, Duke University, Durham, NC, USA.
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
Howard Hughes Medical Institute, Chevy Chase, MD, USA.

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.

中文翻译：

长引发的生发中心具有持久的亲和力成熟和克隆迁移

生发中心是抗体进化的引擎。在这里，我们使用人类免疫缺陷病毒 (HIV) Env 蛋白免疫原在恒河猴中引发，然后长时间不进行进一步免疫，证明生发中心 B (B _GC ) 细胞可持续至少 6 个月。与传统免疫相比，第 10 周时 B _GC细胞增加了 186 倍。单细胞转录谱显示亮区和暗区生发中心状态均得到维持。 B _GC细胞的抗体体细胞超突变在整个 29 周的启动期内持续积累，有选择压力的证据。 29 周时，结合 Env 的 B _GC细胞仍比基线高 49 倍，这表明它们可以在更长的时间内保持活跃。单次加强免疫后产生高滴度的 HIV 中和抗体。完全糖基化的 HIV 三聚体蛋白是一种复杂的抗原，对 B 细胞带来相当大的免疫优势挑战^1,2 。在这些长时间启动条件下产生的记忆 B 细胞具有更高水平的抗体体细胞超突变，并且记忆 B 细胞和抗体都更有可能识别非免疫显性表位。鉴定了许多跨越 6 个月生发中心期的 B _GC细胞谱系系统发育，证明了持续的生发中心活性和选择至少 191 天，没有进一步的抗原暴露。长期、缓慢传递（12 天）的免疫方法有望实现困难的疫苗目标，并表明耐心对于调整生发中心以最大限度地提高抗体反应具有巨大价值。

更新日期：2022-09-22

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