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生发中心 B 细胞之间的亲和力差距驱动 MPER 前体的选择。

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

机构信息

The Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA.

Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.

出版信息

Nat Immunol. 2024 Jun;25(6):1083-1096. doi: 10.1038/s41590-024-01844-7. Epub 2024 May 30.


DOI:10.1038/s41590-024-01844-7
PMID:38816616
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11147770/
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.

摘要

目前,预防人体免疫缺陷病毒 1 (HIV-1) 的疫苗研究旨在引发广泛中和抗体 (bnAbs)。靶向膜近端外区 (MPER) 的 bnAbs,如 10E8,提供了异常广泛的中和作用,但有些是自身反应性的。在这里,我们生成了人源化 B 细胞抗原受体嵌合小鼠模型,以测试一系列针对种系的免疫原是否可以将 MPER 特异性前体引导至 bnAbs。我们发现,10E8 前体募集到生发中心 (GC) 需要对种系靶向免疫原具有最低亲和力,但由于高亲和力内源性 B 细胞竞争物的置换,MPER 前体在 GC 中的驻留时间很短。更高亲和力的种系靶向免疫原延长了 MPER 前体的 GC 驻留时间,但只有在 MPER-HuGL18 中观察到了强大的长期 GC 驻留和成熟,MPER-HuGL18 是一种能够在 GC 中与内源性 B 细胞竞争物缩小亲和力差距的 MPER 前体克隆型。因此,种系靶向免疫原可以诱导靶向 MPER 的抗体,而 GC 中的 B 细胞驻留可能受前体-竞争物亲和力差距的调节。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c99/11147770/47869f1e9934/41590_2024_1844_Fig18_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c99/11147770/eb32e5748184/41590_2024_1844_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c99/11147770/ffe8a1db4a17/41590_2024_1844_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c99/11147770/70eb68e7116d/41590_2024_1844_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c99/11147770/b401bda1e48f/41590_2024_1844_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c99/11147770/552ac4c5cbda/41590_2024_1844_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c99/11147770/966ba2bb9f6f/41590_2024_1844_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c99/11147770/7a6d9437f260/41590_2024_1844_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c99/11147770/c95718fe36d7/41590_2024_1844_Fig13_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c99/11147770/11baaa0f7834/41590_2024_1844_Fig14_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c99/11147770/e22c72cd5403/41590_2024_1844_Fig15_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c99/11147770/51e132368e95/41590_2024_1844_Fig16_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c99/11147770/23a62bb373ef/41590_2024_1844_Fig17_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c99/11147770/47869f1e9934/41590_2024_1844_Fig18_ESM.jpg

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bioRxiv. 2025-8-19

[2]
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Proc Natl Acad Sci U S A. 2025-8-19

[3]
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[4]
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[5]
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[6]
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bioRxiv. 2025-5-27

[7]
Diverse priming outcomes under conditions of very rare precursor B cells.

Immunity. 2025-4-8

[8]
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[9]
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[10]
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本文引用的文献

[1]
Antibody production relies on the tRNA inosine wobble modification to meet biased codon demand.

Science. 2024-1-12

[2]
ARMADiLLO: a web server for analyzing antibody mutation probabilities.

Nucleic Acids Res. 2023-7-5

[3]
Vaccination induces HIV broadly neutralizing antibody precursors in humans.

Science. 2022-12-2

[4]
Membrane-bound mRNA immunogens lower the threshold to activate HIV Env V2 apex-directed broadly neutralizing B cell precursors in humanized mice.

Immunity. 2022-11-8

[5]
Human immunoglobulin repertoire analysis guides design of vaccine priming immunogens targeting HIV V2-apex broadly neutralizing antibody precursors.

Immunity. 2022-11-8

[6]
Vaccination in a humanized mouse model elicits highly protective PfCSP-targeting anti-malarial antibodies.

Immunity. 2021-12-14

[7]
Emerging concepts in the science of vaccine adjuvants.

Nat Rev Drug Discov. 2021-6

[8]
Multiplexed CRISPR/CAS9-mediated engineering of pre-clinical mouse models bearing native human B cell receptors.

EMBO J. 2021-1-15

[9]
Antibody Affinity Shapes the Choice between Memory and Germinal Center B Cell Fates.

Cell. 2020-11-25

[10]
B cells expressing authentic naive human VRC01-class BCRs can be recruited to germinal centers and affinity mature in multiple independent mouse models.

Proc Natl Acad Sci U S A. 2020-9-1

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