Structural cells are key regulators of organ-specific immune response

The mammalian immune system implements a remarkably effective set of mechanisms for fighting pathogens. Its main actors are hematopoietic immune cells, including myeloid cells with their focus on innate immunity and lymphoid cells as enablers of adaptive immunity. Nevertheless, immune functions are not unique to hematopoietic cells, and basic mechanisms of pathogen defense are present in many other cell types. To advance our understanding of immunology outside of the hematopoietic system, we systematically investigated immune gene regulation in the three major types of structural cells: Epithelium, endothelium, and fibroblasts. We characterized these cell types across 12 organs in mice, using cellular phenotyping, transcriptome sequencing, chromatin accessibility profiling, and epigenome mapping. This comprehensive dataset uncovered a striking complexity of immune gene activity and regulation in structural cells. The observed patterns were highly organ-specific and appear to modulate interactions between structural cells and hematopoietic immune cells. Moreover, we identified an epigenetically encoded immune potential in structural cells under tissue homeostasis, which was triggered in response to systemic viral infection. This study highlights an underappreciated complexity of organ-specific immune gene regulation beyond hematopoietic cells, and it provides a high-resolution, multi-omics atlas of the epigenomic and transcription-regulatory circuitry of structural cells in the mouse. 71 ChIPseq (ChIPmentation) samples with antibodies for H3K4me2 in 3 types of structural cells (endothelium, epithelium, fibroblasts) sort-purified from 12 organs in mice.