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Original research
Very early-life exposure to microbiota-induced TNF drives the maturation of neonatal pre-cDC1
  1. Arnaud Köhler1,2,
  2. Sandrine Delbauve1,2,
  3. Justine Smout1,2,
  4. David Torres1,2,
  5. Véronique Flamand1,2
  1. 1Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium
  2. 2ULB Center for Research in Immunology (U-CRI), Gosselies, Belgium
  1. Correspondence to Professor Véronique Flamand, Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium; vflamand{at}ulb.ac.be

Abstract

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.

  • antibiotics
  • bacterial infection
  • dendritic cells
  • TNF-alpha
  • immunoregulation
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Footnotes

  • Contributors AK conducted most of the experiments and performed the bioinformatics analysis. DT, JS and SD contributed to some experiments. AK, SD, DT and JS analysed the data and prepared the figures. DT provided input for research design with the infectious model. AK and VF wrote the article. VF supervised the work. All authors have approved the final version of this manuscript.

  • Funding This study was supported by the Fonds National de la Recherche Scientifique-crédits de recherche (FNRS-CDR, Belgium), the "Actions de Recherches Concertées" and the Service Public de Wallonie – FEDER Wallonia – Biomed portfolio.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as online supplementary information.

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