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Mucosal or systemic microbiota exposures shape the B cell repertoire
Nature ( IF 64.8 ) Pub Date : 2020-08-05 , DOI: 10.1038/s41586-020-2564-6
Hai Li 1 , Julien P Limenitakis 1 , Victor Greiff 2 , Bahtiyar Yilmaz 1 , Olivier Schären 3 , Camilla Urbaniak 4 , Mirjam Zünd 1 , Melissa A E Lawson 1 , Ian D Young 1 , Sandra Rupp 1 , Mathias Heikenwälder 5 , Kathy D McCoy 1 , Siegfried Hapfelmeier 3 , Stephanie C Ganal-Vonarburg 1 , Andrew J Macpherson 1
Affiliation  

Colonization by the microbiota causes a marked stimulation of B cells and induction of immunoglobulin, but mammals colonized with many taxa have highly complex and individualized immunoglobulin repertoires 1 , 2 . Here we use a simplified model of defined transient exposures to different microbial taxa in germ-free mice 3 to deconstruct how the microbiota shapes the B cell pool and its functional responsiveness. We followed the development of the immunoglobulin repertoire in B cell populations, as well as single cells by deep sequencing. Microbial exposures at the intestinal mucosa generated oligoclonal responses that differed from those of germ-free mice, and from the diverse repertoire that was generated after intravenous systemic exposure to microbiota. The IgA repertoire—predominantly to cell-surface antigens—did not expand after dose escalation, whereas increased systemic exposure broadened the IgG repertoire to both microbial cytoplasmic and cell-surface antigens. These microbial exposures induced characteristic immunoglobulin heavy-chain repertoires in B cells, mainly at memory and plasma cell stages. Whereas sequential systemic exposure to different microbial taxa diversified the IgG repertoire and facilitated alternative specific responses, sequential mucosal exposure produced limited overlapping repertoires and the attrition of initial IgA binding specificities. This shows a contrast between a flexible response to systemic exposure with the need to avoid fatal sepsis, and a restricted response to mucosal exposure that reflects the generic nature of host–microbial mutualism in the mucosa. A mouse model of systemic versus mucosal exposure to microbial taxa reveals that the former provokes a flexible B cell response with a diverse immunoglobulin repertoire, whereas the latter generates a more-restricted response.

中文翻译:

粘膜或全身微生物群暴露塑造 B 细胞库

微生物群的定植会导致 B 细胞的显着刺激和免疫球蛋白的诱导,但被许多分类群定植的哺乳动物具有高度复杂和个性化的免疫球蛋白库 1, 2。在这里,我们使用定义的瞬时暴露于无菌小鼠不同微生物分类群的简化模型 3 来解构微生物群如何塑造 B 细胞库及其功能响应。我们通过深度测序跟踪了 B 细胞群以及单细胞中免疫球蛋白库的发展。肠道黏膜的微生物暴露产生了不同于无菌小鼠的寡克隆反应,也不同于静脉全身暴露于微生物群后产生的多种反应。IgA 库——主要是细胞表面抗原——在剂量增加后没有扩大,而增加全身暴露使 IgG 库扩大到微生物细胞质和细胞表面抗原。这些微生物暴露在 B 细胞中诱导了特征性的免疫球蛋白重链库,主要是在记忆和浆细胞阶段。虽然连续全身暴露于不同微生物分类群使 IgG 库多样化并促进替代特异性反应,但连续粘膜暴露产生有限的重叠库和初始 IgA 结合特异性的磨损。这显示了对全身暴露的灵活反应与避免致命性败血症的需要之间的对比,以及对粘膜暴露的有限反应,反映了粘膜中宿主-微生物共生的一般性质。
更新日期:2020-08-05
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