Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium.
ULB Center for Research in Immunology (U-CRI), Gosselies, Belgium.
Gut. 2021 Mar;70(3):511-521. doi: 10.1136/gutjnl-2019-319700. Epub 2020 Jun 16.
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.
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 was monitored.
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 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.
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.
在以抗炎和耐受免疫为主导的新生儿期，诱导针对病原体的免疫保护尤为重要。本临床前研究旨在确定环境因素（如微生物群）是否通过影响 1 型传统树突状细胞（pre-cDC1）前体的发育和功能成熟，从而影响早期生命免疫。
确定来自接受抗生素治疗母亲的新生儿脾脏中的 pre-cDC1 表型和细胞因子表达。在体外和体内测试了髓样细胞来源的肿瘤坏死因子（TNF）的作用。对新生儿分选的 pre-cDC1 进行 RNA 测序分析。监测了针对 的早期保护性 CD8 T 细胞反应。
我们观察到，首次接触微生物群体会在出生后不久促进单核细胞和巨噬细胞分泌 TNF。我们证明，这种髓样来源的炎症性细胞因子对于诱导这些新生儿调节性 pre-cDC1 的成熟至关重要。髓样 TNF 信号转导作用于 C1q 和 β-连环蛋白途径，并改变新生儿 pre-cDC1 的脂肪酸代谢。此外，我们还表明，在新生儿 感染期间，与微生物群相关的髓样 TNF 通过调节其分泌白细胞介素 10（IL-10）和 IL-12p40 的能力，促进这些 pre-cDC1 诱导保护性 CD8 T 细胞反应的能力。
我们的研究结果强调了微生物群衍生的 TNF 启动新生儿脾脏 pre-cDC1 区室分化和功能成熟的作用。它们使我们更好地理解了早期生命中与微生物群相关的免疫功能障碍的潜在机制。
