小柯机器人

科学家发现具有持久亲和力成熟和克隆迁移的长活化生发中心
2022-09-25 16:32

美国拉霍亚免疫学研究所Shane Crotty研究团队发现具有持久亲和力成熟和克隆迁移的长活化生发中心。相关论文于2022年9月21日在线发表在《自然》杂志上。

研究人员使用人类免疫缺陷病毒(HIV)Env蛋白免疫原引诱了恒河猴,然后长期不进一步免疫,证明生发中心B(BGC)细胞至少持续了6个月。与常规免疫相比,到第10周,BGC细胞增加了186倍。单细胞转录分析显示,明区和暗区的生发中心状态都是持续的。在整个29周的诱导期,BGC细胞的抗体体细胞高突变继续积累,有证据表明存在选择压力。在29周时,与Env结合的BGC细胞仍比基线高出49倍,这表明它们可以在更长时间内保持活性。

在一次加强免疫后,产生了高滴度的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细胞构成相当大的免疫优势挑战。在这些长活化条件下产生的记忆B细胞具有更高水平的抗体体细胞超突变,而且记忆B细胞和抗体都更有可能识别非免疫优势表位。众多的BGC细胞系谱跨越了6个月的生发中心期,显示出持续的生发中心活动和选择至少191天,没有进一步的抗原接触。长时间、缓慢给药(12天)的免疫方法对困难的疫苗靶标有希望,并表明耐心等待对调整生发中心以最大限度地提高抗体反应有很大价值。

据悉,生发中心是抗体演化的引擎。

附:英文原文

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

Author: Lee, Jeong Hyun, Sutton, Henry J., Cottrell, Christopher A., Phung, Ivy, Ozorowski, Gabriel, Sewall, Leigh M., Nedellec, Rebecca, Nakao, Catherine, Silva, Murillo, Richey, Sara T., Torre, Jonathan L., Lee, Wen-Hsin, Georgeson, Erik, Kubitz, Michael, Hodges, Sam, Mullen, Tina-Marie, Adachi, Yumiko, Cirelli, Kimberly M., Kaur, Amitinder, Allers, Carolina, Fahlberg, Marissa, Grasperge, Brooke F., Dufour, Jason P., Schiro, Faith, Aye, Pyone P., Kalyuzhniy, Oleksandr, Liguori, Alessia, Carnathan, Diane G., Silvestri, Guido, Shen, Xiaoying, Montefiori, David C., Veazey, Ronald S., Ward, Andrew B., Hangartner, Lars, Burton, Dennis R., Irvine, Darrell J., Schief, William R., Crotty, Shane

Issue&Volume: 2022-09-21

Abstract: 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(BGC) cells that last for at least 6months. A 186-fold increase in BGC cells was present by week10 compared with conventional immunization. Single-cell transcriptional profiling showed that both light- and dark-zone germinal centre states were sustained. Antibody somatic hypermutation of BGC cells continued to accumulate throughout the 29-week priming period, with evidence of selective pressure. Env-binding BGC cells were still 49-fold above baseline at 29weeks, 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 Bcells1,2. Memory Bcells generated under these long priming conditions had higher levels of antibody somatic hypermutation, and both memory Bcells and antibodies were more likely to recognize non-immunodominant epitopes. Numerous BGC cell lineage phylogenies spanning more than the 6-month germinal centre period were identified, demonstrating continuous germinal centre activity and selection for at least 191days with no further antigen exposure. A long-prime, slow-delivery (12days) 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.

DOI: 10.1038/s41586-022-05216-9

Source: https://www.nature.com/articles/s41586-022-05216-9

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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