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

Laura Schaupp,Pawel Durek,Leif Rogell,Kristian Schütze,Felix Melchior,Tobias Hain,Ulrike Grundmann,Gitta Anne Heinz,Sven Jäckel,Julia Spanier,Andreas Diefenbach,Andrew J Macpherson,Martina Dorsch,Tobias Bopp,Michael Kofoed-Branzk,Oliver Kretz,Karsten Mahnke,Tobias B Huber,Ulrich Kalinke,Christoph Wilhelm,Sven Danckwardt,Hansjörg Schild,Sabine Muth,Thomas Schwanz,Fabian Guendel,Matthias Klein,Stefan Lienenklaus,Mir‐Farzin Mashreghi ,Siegfried Weiß ,Verena Schmitt ,Carsten Reinhardt ,Stephanie C Ganal‐Vonarburg ,Pia‐Katharina Larsen ,Hans Probst

doi:10.1016/j.cell.2020.04.022

Abstract

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 Tcell 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.

Highlights

Border surfaces of multicellular organisms are colonized by a complex ecosystem composed of bacteria, viruses, and fungi, collectively referred to as the microbiota (Blander et al, 2017; Hooper and Macpherson, 2010)
Using genome-wide analysis of transcriptional and epigenetic regulomes of conventional dendritic cells (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
Using genome-wide profiling of cDCs, we demonstrate that microbiota-controlled IFN-I production by plasmacytoid dendritic cells (pDCs) controlled a distinct transcriptional, epigenetic, and metabolic basal state of cDCs, enabling them to provide a powerful response following pathogen encounter, but at the same time, permitting priming of unwanted T cell responses at the steady state

Summary

Introduction

Border surfaces of multicellular organisms are colonized by a complex ecosystem composed of bacteria, viruses, and fungi, collectively referred to as the microbiota (Blander et al, 2017; Hooper and Macpherson, 2010). Microbiota-controlled signaling pathways affect various aspects of host physiology and fitness. We and others have shown that signals of the. 1080 Cell 181, 1080–1096, May 28, 2020 a 2020 Elsevier Inc. Karsten Mahnke, Gitta Anne Heinz, Mir-Farzin Mashreghi, Pawel Durek, Ulrich Kalinke, Oliver Kretz, Tobias B. Huber, Siegfried Weiss, Christoph Wilhelm, Andrew J. Macpherson, Hansjorg Schild,5,6,25,27,28,* Andreas Diefenbach,1,2,3,27,28,29,* and Hans Christian Probst5,6,27,28,*

Methods

Results

Discussion

Conclusion