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RESEARCH PRODUCT

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

Matthias KleinMartina DorschMichael Kofoed-branzkPia-katharina LarsenStephanie C. Ganal-vonarburgLaura SchauppSven JäckelSiegfried WeissAndreas DiefenbachAndrew J. MacphersonVanessa SchmittSabine MuthHans Christian ProbstFelix MelchiorJulia SpanierKristian SchützeThomas SchwanzLeif RogellStefan LienenklausFabian GuendelTobias BoppHansjörg SchildTobias HainMir-farzin MashreghiUlrike GrundmannUlrich KalinkeChristoph ReinhardtPawel DurekKarsten MahnkeSven DanckwardtTobias B. HuberChristoph WilhelmOliver KretzOliver KretzGitta Anne Heinz

subject

MaleReceptor Interferon alpha-betaAdaptive ImmunityCD8-Positive T-LymphocytesBiologyGeneral Biochemistry Genetics and Molecular BiologyMice03 medical and health sciences0302 clinical medicineImmune systemAntigenAnimalsEpigeneticsReceptor030304 developmental biologyEpigenomics0303 health sciencesMicrobiotaPeripheral toleranceDendritic Cellsperipheral toleranceCell biologyMice Inbred C57BLtype I interferonsplasmacytoid dendritic cellsconventional dendritic cellsInterferon Type IFemale030217 neurology & neurosurgerySignal Transduction

description

Summary 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.

yearjournalcountryeditionlanguage
2019-10-27Cell
https://doi.org/10.1016/j.cell.2020.04.022