Schaupp, Muth, and Rogell et al. showed that cDCs of mice lacking commensal microbiota had impaired anti-CD40-induced cytokine responses, reversible by bacterial recolonization. RNAseq, biochemical, and reporter assays showed that microbiota signaled pDCs via pattern recognition receptors to produce basal levels of IFNβ that induced type I IFN receptor-dependent tonic signaling in mature cDCs. This signaling instructed specific epigenomic and metabolic programs that enabled CD8+ T cell priming in a model system with cDC-expressed “self”-antigens. Anti-CD40 stimulation did not overcome impaired cDC response resulting from Type I IFN deficiency.
Contributed by Paula Hochman
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 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.
Author Info: (1) Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charite-Universitatsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany; Ber
Author Info: (1) Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charite-Universitatsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany; Berlin Institute of Health (BIH), Anna-Louisa-Karsch Strasse 2, 10178 Berlin, Germany; Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum, Chariteplatz 1, 10117 Berlin, Germany; Institute for Molecular Biology (IMB), Ackermannweg 4, 55128 Mainz, Germany. (2) Institute of Immunology, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; Research Centre for Immunotherapy, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. (3) Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charite-Universitatsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany; Berlin Institute of Health (BIH), Anna-Louisa-Karsch Strasse 2, 10178 Berlin, Germany; Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum, Chariteplatz 1, 10117 Berlin, Germany; Max-Planck-Institute of Immunobiology and Epigenetics, Stubeweg 51, 79108 Freiburg, Germany. (4) Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charite-Universitatsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany; Berlin Institute of Health (BIH), Anna-Louisa-Karsch Strasse 2, 10178 Berlin, Germany; Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum, Chariteplatz 1, 10117 Berlin, Germany; Max-Planck-Institute of Immunobiology and Epigenetics, Stubeweg 51, 79108 Freiburg, Germany. (5) Institute of Immunology, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; Research Centre for Immunotherapy, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. (6) Institute of Immunology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany; Institute for Laboratory Animal Science, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. (7) Department for BioMedical Research (DBMR), University Clinic for Visceral Surgery and Medicine, Inselspital, University of Bern, Murtenstrasse 35, 3008 Bern, Switzerland. (8) Institute of Immunology, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; Research Centre for Immunotherapy, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. (9) Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charite-Universitatsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany; Berlin Institute of Health (BIH), Anna-Louisa-Karsch Strasse 2, 10178 Berlin, Germany; Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum, Chariteplatz 1, 10117 Berlin, Germany. (10) Institute of Immunology, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; Research Centre for Immunotherapy, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. (11) Institute of Immunology, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; Research Centre for Immunotherapy, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. (12) Institute for Medical Microbiology and Hygiene, University of Freiburg Medical Center, Hermann-Herder-Str. 11, 79104 Freiburg, Germany. (13) Immunopathology Unit, Institute of Clinical Chemistry and Clinical Pharmacology, Medical Faculty, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany. (14) Institute for Laboratory Animal Science, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. (15) Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Feodor-Lynen-Strasse 7, 30625 Hannover, Germany. (16) Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Feodor-Lynen-Strasse 7, 30625 Hannover, Germany. (17) Institute of Medical Microbiology and Hygiene, University Medical Center Mainz, Obere Zahlbacher Strasse 67, 55131 Mainz, Germany. (18) Center for Thrombosis and Hemostasis, University Medical Center, Johannes Gutenberg University of Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. (19) Center for Thrombosis and Hemostasis, University Medical Center, Johannes Gutenberg University of Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. (20) Institute of Immunology, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; Research Centre for Immunotherapy, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; University Cancer Center Mainz, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; German Cancer Consortium (DKTK). (21) Center for Thrombosis and Hemostasis, University Medical Center, Johannes Gutenberg University of Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; Posttranscriptional Gene Regulation, Cancer Research and Experimental Hemostasis, University Medical Centre Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; Institute for Clinical Chemistry and Laboratory Medicine, University Medical Centre Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. (22) Department of Dermatology, Ruprecht-Karls-University Heidelberg, D-69120 Heidelberg, Germany. (23) Therapeutic Gene Regulation, Deutsches Rheuma-Forschungszentrum, Chariteplatz 1, 10117 Berlin, Germany. (24) Therapeutic Gene Regulation, Deutsches Rheuma-Forschungszentrum, Chariteplatz 1, 10117 Berlin, Germany. (25) Therapeutic Gene Regulation, Deutsches Rheuma-Forschungszentrum, Chariteplatz 1, 10117 Berlin, Germany. (26) Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Feodor-Lynen-Strasse 7, 30625 Hannover, Germany; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. (27) III. Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany; Department for Neuroanatomy, Anatomy and Cell Biology, Medical Faculty, University of Freiburg, Freiburg, Germany. (28) III. Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany. (29) Institute of Immunology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. (30) Immunopathology Unit, Institute of Clinical Chemistry and Clinical Pharmacology, Medical Faculty, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany. (31) Department for BioMedical Research (DBMR), University Clinic for Visceral Surgery and Medicine, Inselspital, University of Bern, Murtenstrasse 35, 3008 Bern, Switzerland. (32) Institute of Immunology, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; Research Centre for Immunotherapy, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; Helmholtz Institute Translational Oncology, Obere Zahlbacher Strasse 63, 55131 Mainz, Germany. Electronic address: schild@uni-mainz.de. (33) Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charite-Universitatsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany; Berlin Institute of Health (BIH), Anna-Louisa-Karsch Strasse 2, 10178 Berlin, Germany; Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum, Chariteplatz 1, 10117 Berlin, Germany. Electronic address: andreas.diefenbach@charite.de. (34) Institute of Immunology, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; Research Centre for Immunotherapy, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. Electronic address: hcprobst@uni-mainz.de.
