生命早期菌群促进免疫发育的新机制
创作:大月半 审核:爱的抉择 07月01日
  • 母鼠妊娠晚期施用抗生素,证实菌群的减少会推迟乳鼠早期脾脏中常规树突细胞1(cDC1)的分化;
  • 早期微生物暴露会刺激新生乳鼠脾脏单核细胞和巨噬细胞在生命头3天产生TNF;
  • 髓系来源的TNF信号作用于乳鼠cDC1前体细胞(pre-cDC1)的C1q和β-catenin通路,调控脂肪酸代谢,对限制新生期耐受性环境和调节性pre-cDC1的成熟非常重要;
  • 李斯特菌感染乳鼠,肠道菌群诱导TNF产生,TNF通过调节IL-10和 IL-12p40,诱导保护性CD8+ T细胞响应。
主编推荐语
爱的抉择
在抗炎和耐受免疫为主的新生儿期,诱导对病原体的免疫保护尤为重要。《Gut》近期发表的文章显示,生命早期菌群能刺激新生乳鼠的髓系细胞产生促炎细胞因子TNF,TNF促进调节性pre-cDC1的成熟。此外,在李斯特菌感染模型中,肠道菌群诱导的TNF促进保护性CD8+ T细胞反应,清除病原体。
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Gut [IF:19.819]

Very early-life exposure to microbiota-induced TNF drives the maturation of neonatal pre-cDC1

生命早期暴露于微生物诱导的TNF驱动新生乳鼠pre-cDC1成熟

10.1136/gutjnl-2019-319700

06-16, Article

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Objective: Induction of immune protection against pathogens is particularly crucial during the neonatal period dominated by anti-inflammatory and tolerance immunity. The preclinical study was carried out to determine whether environmental factors such as microbiota may influence early life immunity by impacting the development and the functional maturation of precursors of type 1 conventional dendritic cells (pre-cDC1), endowed with regulatory properties.
Design: Pre-cDC1 phenotype and cytokine expression in the spleen of neonates from antibiotic-treated mothers were established. The role of myeloid-derived tumour necrosis factor (TNF) was tested in vitro and in vivo. RNA sequencing analysis on neonatal sorted pre-cDC1 was performed. The early life protective CD8+ T-cell response against Listeria monocytogenes was monitored.
Results: We observed that first exposure to microbiota promotes TNF secretion by monocytes and macrophages shortly after birth. We demonstrated that this myeloid-derived inflammatory cytokine is crucial to induce the maturation of these neonatal regulatory pre-cDC1. Myeloid TNF signalling acts on C1q and β-catenin pathway and modifies the fatty acid metabolism in neonatal pre-cDC1. Furthermore, we showed that during neonatal L. monocytogenes infection, microbiota-associated myeloid TNF promotes the capacity of these pre-cDC1 to induce protective CD8+ T-cell responses, by modulating their ability to secrete interleukin-10 (IL-10) and IL-12p40.
Conclusion: Our findings emphasise the role of microbiota-derived TNF to kick-start the differentiation and the functional maturation of the neonatal splenic pre-cDC1 compartment. They bring a better understanding of potential mechanisms underlying some microbiota-linked immune dysfunction in early life.

First Authors:
Arnaud Köhler

Correspondence Authors:
Véronique Flamand

All Authors:
Arnaud Köhler,Sandrine Delbauve,Justine Smout,David Torres,Véronique Flamand

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