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Cell . 2020 May 28

Microbiota-Induced Type I Interferons Instruct a Poised Basal State of Dendritic Cells

Christian Kurts, Florent Ginhoux, Ulf Panzer, Elena Mitsi, Beatriz Carniel, Jesús Reiné, Jamie Rylance, Seher Zaidi, Alessandra Soares-Schanoski, Victoria Connor, Andrea M Collins, Andreas Schlitzer, Elissavet Nikolaou, Carla Solórzano, Sherin Pojar, Helen Hill, Angela D Hyder-Wright, Kondwani C Jambo, Marco R Oggioni, Megan De Ste Croix, Stephen B Gordon, Simon P Jochems, Daniela M Ferreira, Stephanie Fischinger, Jonathan K Fallon, Ashlin R Michell, Thomas Broge, Todd J Suscovich, Hendrik Streeck, Galit Alter, Laura Schaupp, Sabine Muth, Leif Rogell, Michael Kofoed-Branzk, Felix Melchior, Stefan Lienenklaus, Stephanie C Ganal-Vonarburg, Matthias Klein, Fabian Guendel, Tobias Hain, Kristian Schütze, Ulrike Grundmann, Vanessa Schmitt, Martina Dorsch, Julia Spanier, Pia-Katharina Larsen, Thomas Schwanz, Sven Jäckel, Christoph Reinhardt, Tobias Bopp, Sven Danckwardt, Karsten Mahnke, Gitta Anne Heinz, Mir-Farzin Mashreghi, Pawel Durek, Ulrich Kalinke, Oliver Kretz, Tobias B Huber, Siegfried Weiss, Christoph Wilhelm, Andrew J Macpherson, Hansjörg Schild, Andreas Diefenbach, Hans Christian Probst

Environmental signals shape host physiology and fitness. Microbiota-derived cues are required to program conventional dendritic cells (cDCs) during the steady state so that they can promptly respond and initiate adaptive immune responses when encountering pathogens. However, the molecular underpinnings of microbiota-guided instructive programs are not well understood. Here, we report that the indigenous microbiota controls constitutive production of type I interferons (IFN-I) by plasmacytoid DCs. Using genome-wide analysis of transcriptional and epigenetic regulomes of cDCs from germ-free and IFN-I receptor (IFNAR)-deficient mice, we found that tonic IFNAR signaling instructs a specific epigenomic and metabolic basal state that poises cDCs for future pathogen combat. However, such beneficial biological function comes with a trade-off. Instructed cDCs can prime T cell responses against harmless peripheral antigens when removing roadblocks of peripheral tolerance. Our data provide fresh insights into the evolutionary trade-offs that come with successful adaptation of vertebrates to their microbial environment.

PMID: 32380006