Induktion und funktionelle Konsequenzen der adaptiven Immunantwort im Neugeborenen-Darm in Homöostase und Infektion
Parasitologie und Biologie der Erreger tropischer Infektionskrankheiten
Zusammenfassung der Projektergebnisse
The complexity of the intestinal immune system in the adult host reflects its task of maintaining homeostasis remaining tolerant to commensal microbiota that is beneficial for the host but mounting vigorous immune responses against incoming pathogens. The colonization process begins at birth but the maturation of the mucosal adaptive immune system is delayed throughout the postnatal period. We have previously identified neonatal regulatory T cells and breast milk IgA as factors contributing to the active suppression of adaptive immune maturation in the neonatal intestine. In the current project we aimed to identify mechanisms that regulate the onset of neonatal immune maturation. We performed comparative transcriptomic, flow cytometric and histological analysis of Peyer’s patch (PP) mononuclear phagocytes (MNP) in the small intestine, the primary inductive site of intestinal immunity. Despite the early presence of MNPs, conventional dendritic cells (cDC) of type 1, 2a and 2b exhibited significant age-dependent differences in cellular composition and tissue distribution. Further, single cell transcriptional profiling and functional assays revealed decreased antimicrobial and antigen processing/presentation capacity, an overall retarded cell maturation and reduced antigen uptake. In cDC2a this resulted in a reduced proportion of CCR7+ migratory cells and a consequent defect in CD4 T cell priming. Surprisingly, metagenomic, metaproteomic, and functional immunological analyses revealed a dense and diverse small intestinal core microbiome early after birth making global lack of bacterial colonization and the resulting lack of bacterial antigen an unlikely reason for delayed postnatal immune maturation. Instead, transcriptional profiling of neonatal DC subsets identified reduced expression of type I interferon (IFN)-stimulated genes (ISG). Type I IFN induction by oral administration of the TLR7 agonist R848 accelerated MNP maturation and enhanced cognate antigen T cell priming. Administration of R848 with oral vaccination modified the cellular and humoral immune response. Together, our results identify MNPs as rate limiting factor of postnatal immune maturation, indicate the biological role of delayed maturation and demonstrate that targeted interventional strategies allow manipulation of mucosal responses in early life.
Projektbezogene Publikationen (Auswahl)
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(2017). Neonatal mucosal immunology. Mucosal Immunol 10, 5-17
Torow, N., Marsland, B.J., Hornef, M.W., and Gollwitzer, E.S.
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(2018). Minimal SPI1-T3SS effector requirement for Salmonella enterocyte invasion and intracellular proliferation in vivo. PLoS Pathog 14, e1006925
Zhang, K., Riba, A., Nietschke, M., Torow, N., Repnik, U., Putz, A., Fulde, M., Dupont, A., Hensel, M., and Hornef, M.
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(2019). The Timed Pathway to Homeostasis. Immunity 50, 1127-1129
Torow, N., and Hornef, M.W.
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(2020). 'Layered immunity' and the 'neonatal window of opportunity' - timed succession of non-redundant phases to establish mucosal host-microbial homeostasis after birth. Immunology 159, 15-25
Hornef, M.W., and Torow, N.
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(2020). Disturbed gut microbiota and bile homeostasis in Giardia-infected mice contributes to metabolic dysregulation and growth impairment. Sci Transl Med 12
Riba, A., Hassani, K., Walker, A., van Best, N., von Zeschwitz, D., Anslinger, T., Sillner, N., Rosenhain, S., Eibach, D., Maiga-Ascofare, O., et al.
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(2021). Spatial and temporal key steps in early-life intestinal immune system development and education. FEBS J.
Wagner, C., Torow, N., Hornef, M.W., and Lelouard, H.
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(2022). Neonatal Peyer’s patch cDC activation as a pacemaker of postnatal immune maturation
Torow, N., Li, R., Hitch, T., Mingels, C., Bounny, S. al, van Best, N., Stange, E.-L., Benabid, A., Rüttger, L., Gadermayr, M., et al.
