Toll-like receptor mediated inflammation directs B cells towards protective antiviral extrafollicular responses.
Toll-like receptor mediated inflammation directs B cells towards protective antiviral extrafollicular responses.
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DOI：
10.1038/s41467-023-39734-5
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发表时间：
2023-07-05
影响因子：
16.6
通讯作者：
Baumgarth N
中科院分区：
文献类型：
--
作者：
Lam JH;Baumgarth N
卵泡外成浆细胞反应(EFR)被认为是产生低亲和力的抗体，对感染几乎没有保护作用。矛盾的是，高亲和力的抗原-B细胞受体结合被认为是B细胞分化的主要驱动力，无论是在EFR还是发育较慢的生发中心(GC)。在这里，我们表明，流感感染迅速诱导EFR，通过Toll样受体(TLR)介导的B细胞内在和外在机制产生保护性抗体。B细胞固有的TLR信号支持抗原刺激的B细胞存活、克隆性增殖和B细胞的分化，途径是通过激活核因子-kB c-Rel诱导B细胞分化的主要调节因子IRF4。在免疫后提供持续的TLR4刺激，将病毒特异性B细胞的命运转移到EFRs而不是GC，促使快速产生抗体，并提高它们相对于单独注射抗原/明矾的保护能力。因此，炎症信号作为B细胞命运的决定因素，快速产生保护性的抗病毒卵泡外反应。与生发中心相比，卵泡外成浆细胞反应被认为产生亲和力较低的抗体，几乎不能提供免受感染的保护。在这里，作者在流感感染和免疫的小鼠模型中表明，毛囊外反应可以产生保护性抗体，它们的发展依赖于通过Toll样受体刺激提供的信号。
Extrafollicular plasmablast responses (EFRs) are considered to generate antibodies of low affinity that offer little protection from infections. Paradoxically, high avidity antigen-B cell receptor engagement is thought to be the main driver of B cell differentiation, whether in EFRs or slower-developing germinal centers (GCs). Here we show that influenza infection rapidly induces EFRs, generating protective antibodies via Toll-like receptor (TLR)-mediated mechanisms that are both B cell intrinsic and extrinsic. B cell-intrinsic TLR signals support antigen-stimulated B cell survival, clonal expansion, and the differentiation of B cells via induction of IRF4, the master regulator of B cell differentiation, through activation of NF-kB c-Rel. Provision of sustained TLR4 stimulation after immunization shifts the fate of virus-specific B cells towards EFRs instead of GCs, prompting rapid antibody production and improving their protective capacity over antigen/alum administration alone. Thus, inflammatory signals act as B cell fate-determinants for the rapid generation of protective antiviral extrafollicular responses. Compared to germinal centres, extrafollicular plasmablast responses are thought to produce lower affinity antibodies, offering little protection from infection. Here authors show in an influenza infection and immunization mouse model that extrafollicular responses could yield protective antibodies, and that their development depends on signals provided via Toll-like receptor stimulation.
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影响因子：
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作者：
Grumont, R J;Gerondakis, S
通讯作者：
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作者：
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影响因子：
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作者：
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作者：
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