The Ragon Institute of Massachusetts General Hospital, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA.
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Immunity. 2022 Sep 13;55(9):1693-1709.e8. doi: 10.1016/j.immuni.2022.07.006. Epub 2022 Aug 10.
Human broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin stalk of group 1 influenza A viruses (IAVs) are biased for IGHV1-69 alleles that use phenylalanine (F54) but not leucine (L54) within their CDRH2 loops. Despite this, we demonstrated that both alleles encode for human IAV bnAbs that employ structurally convergent modes of contact to the same epitope. To resolve differences in lineage expandability, we compared F54 versus L54 as substrate within humanized mice, where antibodies develop with human-like CDRH3 diversity but are restricted to single V genes. While both alleles encoded for bnAb precursors, only F54 IGHV1-69 supported elicitation of heterosubtypic serum bnAbs following immunization with a stalk-only nanoparticle vaccine. L54 IGHV1-69 was unproductive, co-encoding for anergic B cells and autoreactive stalk antibodies that were cleared from B cell memory. Moreover, human stalk antibodies also demonstrated L54-dependent autoreactivity. Therefore, IGHV1-69 polymorphism, which is skewed ethnically, gates tolerance and vaccine expandability of influenza bnAbs.
人类针对 1 型流感病毒（IAV）血凝素茎部的广谱中和抗体（bnAbs）偏向于使用苯丙氨酸（F54）而非亮氨酸（L54）的 IGHV1-69 等位基因。尽管如此，我们证明这两种等位基因都编码了人类 IAV bnAbs，它们采用结构上相似的方式与同一表位结合。为了解决谱系扩展性的差异，我们在人源化小鼠中比较了 F54 与 L54 作为底物的情况，在这些小鼠中，抗体的产生具有类似于人类的 CDRH3 多样性，但受到单个 V 基因的限制。虽然这两种等位基因都编码了 bnAb 前体，但只有 F54 IGHV1-69 在接种仅含茎部的纳米颗粒疫苗后，能够诱导产生异源血清 bnAb。L54 IGHV1-69 没有产生作用，同时编码了无反应性 B 细胞和自身反应性茎部抗体，这些抗体从 B 细胞记忆中被清除。此外，人类茎部抗体也表现出 L54 依赖性的自身反应性。因此，IGHV1-69 多态性在种族上存在偏向性，决定了流感 bnAbs 的耐受性和疫苗扩展性。
