Microbiota-induced tonic type I interferons instruct a transcriptional, epigenetic and metabolic program that defines the poised basal state of conventional dendritic cells
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Abstract
Border surfaces in the human body are colonized in high density by various microbes, known as microbiota. It has becoming increasingly clear that, depending on environmental factors and host genetics, the microbiota has profound effects on shaping host physiology, including the education of the host’s immune system.
In my dissertation, I present evidence that microbiota-derived signals are required to program splenic conventional dendritic cells (cDCs) during steady-state, so that they can immediately respond to pathogen encounter by producing pro-inflammatory cytokines and activating T cells.
The molecular mechanisms behind this microbiota-dependent instructive program of cDCs are not well understood though. Here, type I interferons (IFNs), which are constantly produced in steady-state by mainly plasmacytoid (p)DCs, are identified as signaling molecules required for the cDC instruction process. Transcriptome and epigenome analyses revealed that tonic type I IFN receptor signaling instructs a specific epigenetic and metabolic basal state in cDCs that is indispensable for their functionality in pathogen defense.
Collectively, I provide new insights into how the indigenous microbiota affects immunological functions of cDCs residing in non-mucosal tissue on a transcriptional, epigenetic and metabolic level, contributing to a better understanding of the evolutionary trade-offs that come with the successful adaptation of vertebrates to their microbial environment.