美国麻省理工学院和哈佛大学拉贡研究所Facundo D. Batista和William R. Schief团队合作的研究表明，生发中心B细胞间的亲和力差异调控近膜端外部区域（MPER）前体选择。该项研究成果发表在2024年5月30日出版的《自然-免疫学》上。

研究人员建立了人源化B细胞抗原受体基因敲入小鼠模型，以检验一系列种系靶向免疫原是否能诱导 MPER 特异性前体向广泛中和抗体（bnAbs）分化。研究发现，招募10E8前体到生发中心（GC）需要对生发中心靶点免疫原具有最低的亲和力，但由于被亲和力更高的内源性B细胞竞争者所取代，MPER前体在生发中心的驻留时间很短。

亲和力更高的种系靶向免疫原延长了MPER前体在GC的驻留时间，但只有MPER-HuGL18能观察到稳定且长期的GC驻留和成熟，MPER-HuGL18是一种能缩小与GC中内源性B细胞竞争亲和力差距的MPER前体克隆型。因此，种系靶向免疫原可以诱导MPER靶向抗体，而B细胞在GC中的驻留可能受到前体-竞争者亲和力差异的调节。

据了解，针对人类免疫缺陷病毒1（HIV-1）的预防性疫苗旨在激发bnAbs。以MPER为靶点的bnAbs（如10E8）可提供异常广泛的中和作用，但其中一些具有自身反应性。

附：英文原文

Title: Affinity gaps among B cells in germinal centers drive the selection of MPER precursors

Author: Ray, Rashmi, Schiffner, Torben, Wang, Xuesong, Yan, Yu, Rantalainen, Kimmo, Lee, Chang-Chun David, Parikh, Shivang, Reyes, Raphael A., Dale, Gordon A., Lin, Ying-Cing, Pecetta, Simone, Giguere, Sophie, Swanson, Olivia, Kratochvil, Sven, Melzi, Eleonora, Phung, Ivy, Madungwe, Lisa, Kalyuzhniy, Oleksandr, Warner, John, Weldon, Stephanie R., Tingle, Ryan, Lamperti, Edward, Kirsch, Kathrin H., Phelps, Nicole, Georgeson, Erik, Adachi, Yumiko, Kubitz, Michael, Nair, Usha, Crotty, Shane, Wilson, Ian A., Schief, William R., Batista, Facundo D.

Issue&Volume: 2024-05-30

Abstract: Current prophylactic human immunodeficiency virus 1 (HIV-1) vaccine research aims to elicit broadly neutralizing antibodies (bnAbs). Membrane-proximal external region (MPER)-targeting bnAbs, such as 10E8, provide exceptionally broad neutralization, but some are autoreactive. Here, we generated humanized B cell antigen receptor knock-in mouse models to test whether a series of germline-targeting immunogens could drive MPER-specific precursors toward bnAbs. We found that recruitment of 10E8 precursors to germinal centers (GCs) required a minimum affinity for germline-targeting immunogens, but the GC residency of MPER precursors was brief due to displacement by higher-affinity endogenous B cell competitors. Higher-affinity germline-targeting immunogens extended the GC residency of MPER precursors, but robust long-term GC residency and maturation were only observed for MPER-HuGL18, an MPER precursor clonotype able to close the affinity gap with endogenous B cell competitors in the GC. Thus, germline-targeting immunogens could induce MPER-targeting antibodies, and B cell residency in the GC may be regulated by a precursor–competitor affinity gap.

DOI: 10.1038/s41590-024-01844-7

Source: https://www.nature.com/articles/s41590-024-01844-7