Structural cells are key regulators of organ-specific immune responses

Abstract

The mammalian immune system implements a remarkably effective set of mechanisms for fighting pathogens 1 . Its main components are hematopoietic immune cells, including myeloid cells that control innate immunity and lymphoid cells that constitute adaptive immunity 2 . However, immune functions are not unique to hematopoietic cells, and many other cell types display basic mechanisms of pathogen defence 3 – 5 . To advance our understanding of immunology outside the haematopoietic system, here we systematically investigate the regulation of immune genes in the three major types of structural cells: epithelium, endothelium, and fibroblasts. We characterize these cell types across twelve organs in mice, using cellular phenotyping, transcriptome sequencing, chromatin-accessibility profiling, and epigenome mapping. This comprehensive dataset revealed complex immune gene activity and regulation in structural cells. The observed patterns were highly organ-specific and seem to modulate the extensive interactions between structural cells and haematopoietic 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 the prevalence and organ-specific complexity of immune gene activity in non-haematopoietic structural cells, and it provides a high-resolution, multi-omics atlas of the epigenetic and transcriptional networks that regulate structural cells in the mouse.

Single cell RNA sequencing redefines the mesenchymal cell landscape of mouse endometrium

“…Notably, although this study did not include reproductive tissues such as the uterus, many of the identified immune genes and associated GOBP terms are reflected in our scRNAseq results, primarily enriched in F1 (defence response to virus, cellular response to IFNg, antigen processing and presentation). Our results further suggest that such roles can be attributed to specific subpopulations of cells, something that is not accounted for by methods employed by Krausgruber et al However, both reports highlight that structural cell populations may have previously underappreciated roles in tissue homeostasis out with the typical barrier/connective tissue functions (Krausgruber et al 2020).…”

“…A role for human eSFs in modulating the immune response has been described using an in vitro co-culture system (Queckborner, et al 2020). More recently, using an elegant multi-omics profiling and integrative bioinformatics approach, an important role for so called structural cells (endothelial, epithelial cells; fibroblasts) in immune cell regulation has been confirmed in 12 organs of the mouse, during both homeostasis and in response to immunological challenges (Krausgruber, et al 2020). Notably, although this study did not include reproductive tissues such as the uterus, many of the identified immune genes and associated GOBP terms are reflected in our scRNAseq results, primarily enriched in F1 (defence response to virus, cellular response to IFNg, antigen processing and presentation).…”

Major histocompatibility complexes are up‐regulated in glomerular endothelial cells via activation of c‐Jun N‐terminal kinase in 5/6 nephrectomy mice

“…Human endothelial cells express leukocyte function antigen-3, but not CD80, and can induce allorecognition of CD8 + and CD4 + cells (Hughes, Savage, & Pober, 1990). (Krausgruber et al, 2020). Of note, the protective effects of JNK inhibition in both endothelial cells and infiltrating lymphocytes observed here provide valuable information for the treatment of chronic nephritis and renal transplantation.…”

Longitudinal single-cell immune profiling revealed distinct innate immune response in asymptomatic COVID-19 patients

“…We observed an upregulated expression of COL6A3 in CD4 + effector T cells and NK cells of asymptomatic conditions. COL6A3 encodes type VI collagen, and the expression of collagens in structure cells is expected to enhance their ability to interact with hematopoietic cells (Krausgruber et al, 2020). However, the expression of collagens in immune cells is less discussed, and we suspect they might also facilitate better interaction with structure cells.…”