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Structural cells are key regulators of organ-specific immune responses
Open accessAbstract
The mammalian immune system implements a remarkably effective set of mechanisms for fighting pathogens1. Its main components are haematopoietic immune cells, including myeloid cells that control innate immunity, and lymphoid cells that constitute adaptive immunity2. However, immune functions are not unique to haematopoietic cells, and many other cell types display basic mechanisms of pathogen defence3–5. 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. Structural cells implement a broad range of immune-regulatory functions beyond their roles as barriers and connective tissues, and they utilize an epigenetically encoded potential for immune gene activation in their rapid response to viral infection.
Overview
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TL;DR
This study profiles endothelium, epithelium, and fibroblasts across 12 mouse organs and shows that structural cells have widespread, organ-specific immune gene activity and an epigenetically encoded immune potential. This potential is preferentially realized after systemic viral infection and cytokine treatment.
Key findings
- Multi-omics profiling of three structural cell types across 12 mouse organs revealed extensive cell-type-specific and organ-specific immune gene activity; structural cells from the same organ were globally more similar to each other than to the same cell type across organs.
- The authors identified 1,665 genes with unrealized epigenetic potential, of which 335 were annotated with at least one immunological term (odds ratio 1.37, P < 10−5, Fisher’s exact test).
- Genes with unrealized epigenetic potential were overrepresented among genes upregulated after LCMV infection, with the strongest association in liver, lung, and spleen.
- In cytokine-treatment experiments, IFN-α had the strongest effect; for five of six cytokines (not including IL-3), upregulated genes in spleen endothelium significantly overlapped with genes carrying unrealized epigenetic potential under homeostasis.
Methods
- C57BL/6J male mice (8–13 weeks old) were used under homeostatic conditions, after intravenous LCMV Clone 13 infection (2×10⁶ focus-forming units, day 8), or after intravenous cytokine treatment (100 μg/kg; IFN-α, IFN-γ, IL-3, IL-6, TGF-β, or TNF; 2 h).
- Structural cells were purified by standardized FACS sorting using CD31, EpCAM, and GP38 across 12 organs and profiled by Smart-seq2 RNA-seq, ATAC-seq, and H3K4me2 ChIPmentation.
- Integrative bioinformatics included limma-based differential analysis, Fisher’s exact tests, HOMER motif analysis, gene-regulatory network inference, and receptor–ligand interaction prediction; findings were independently checked against the Tabula Muris dataset.
Limitations
- The paper states that inferred cell–cell interactions were not experimentally validated, that LCMV viral load was measured by bulk-tissue qPCR and cannot precisely account for organ-specific susceptible-cell frequencies, and that sample size was not statistically predetermined, experiments were not randomized, and investigators were not blinded.
- The paper notes that structural cells were not well covered in the Tabula Muris validation dataset, and that for lymph node endothelium and thymus fibroblasts only one high-quality ChIPmentation profile could be obtained.
- Evident from the text: the study is limited to mice, uses male mice, and was performed under specific pathogen-free conditions, which may restrict generalizability.
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62 Own result · 31 Own method · 16 Own interpretation · 5 Not checked yet
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In the paper
“Moreover, we identified an epigenetically encoded immune potential in structural cells under tissue homeostasis, which was triggered in response to systemic viral infection.”
§ Structural cells are key regulators of organ-specific immune response > Abstract
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“We observed widespread expression of immune regulators and cytokine signaling molecules in structural cells, organ-specific adaptation to the tissue environment, and unexpectedly diverse capabilities for interacting with hematopoietic cells.”
§ Structural cells are key regulators of organ-specific immune response > Abstract
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In the paper
“Differences across cell types and organs were driven by the characteristic expression patterns of cell-surface proteins and secreted factors in structural cells (Fig. 2b).”
§ Structural cells are key regulators of organ-specific immune response > Results > Immune gene activity in structural cells
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“The resulting cell–cell interaction network (Fig. 2a, Supplementary Table 3) predicted frequent crosstalk between structural cells and haematopoietic cells under homeostasis (Fig. 2a, Extended Data Fig. 4a).”
§ Structural cells are key regulators of organ-specific immune response > Results > Immune gene activity in structural cells
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- Rests on an assumption: Expression of a receptor and its ligand in structural and hematopoietic cells implies potential cell-cell interaction.
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In the paper
“Most notably, we found evidence of an epigenetically encoded immune potential under homeostatic conditions, and the affected genes were preferentially upregulated in response to an immunological challenge induced by systemic viral infection.”
§ Structural cells are key regulators of organ-specific immune response > Abstract
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In the paper
“This comprehensive dataset revealed complex immune gene activity and regulation in structural cells.”
§ Structural cells are key regulators of organ-specific immune response > Abstract
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“These cell-type-specific and organ-specific differences in immune gene activity were reflected by characteristic patterns of chromatin regulation.”
§ Structural cells are key regulators of organ-specific immune response > Abstract
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In the paper
“We observed widespread expression of immune regulators and cytokine signaling molecules in structural cells, organ-specific adaptation to the tissue environment, and unexpectedly diverse capabilities for interacting with hematopoietic cells.”
§ Structural cells are key regulators of organ-specific immune response > Abstract
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In the paper
“Our multi-omics profiles for endothelium, epithelium and fibroblasts across 12 mouse organs thus uncover a marked degree of organ-specific differences among structural cells.”
§ Structural cells are key regulators of organ-specific immune response > Results > Mapping structural cells across organs
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In the paper
“Moreover, we identified an epigenetically encoded immune potential in structural cells under tissue homeostasis, which was triggered in response to systemic viral infection.”
§ Structural cells are key regulators of organ-specific immune response > Abstract
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Most notably, we found evidence of an epigenetically encoded immune potential under homeostatic conditions, and the affected genes were preferentially upregulated in response to an immunological challenge induced by systemic viral infection.”
§ Structural cells are key regulators of organ-specific immune response > Abstract
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“We observed widespread expression of immune regulators and cytokine signaling molecules in structural cells, organ-specific adaptation to the tissue environment, and unexpectedly diverse capabilities for interacting with hematopoietic cells.”
§ Structural cells are key regulators of organ-specific immune response > Abstract
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“Notably, the expression profiles of structural cells within the same organ were globally more similar to each other than structural cells of the same type across organs (Fig. 1d, e, Extended Data Fig. 3d), which suggests that the tissue and organ environment has a major effect on the transcriptomes of structural cells.”
§ Structural cells are key regulators of organ-specific immune response > Results > Mapping structural cells across organs
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“Shared across all types of structural cells, we observed high expression of the inflammatory mediators Apoe, S100a8, and S100a9.”
§ Structural cells are key regulators of organ-specific immune response > Results > Immune gene activity in structural cells
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“For example, strong expression of collagens (Col4a3, Col4a4, Col5a1, Col6a1, Col12a1) and of complement component 3 (C3) in fibroblasts is expected to enhance their ability to interact with hematopoietic cells; high levels of Muc2 and Arg2 in the digestive tract fosters interactions with macrophages and NK cells; and Ccl25 expression in thymus epithelium contributes to the maturation of T cells.”
§ Structural cells are key regulators of organ-specific immune response > Results > Immune gene activity in structural cells
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“Finally, E-cadherin could not enhance or replace our sorting of epithelium as EpCAM+ cells.”
§ Structural cells are key regulators of organ-specific immune response > Results > Mapping structural cells across organs
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“In summary, our study uncovered widespread immune gene regulation in structural cells of the mouse, and it established a multi-organ atlas of the underlying epigenetic and transcription-regulatory programs.”
§ Structural cells are key regulators of organ-specific immune response > Abstract
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“Alternative endothelial markers such as CD144 (VE-cadherin), MAdCAM1 and VCAM1 (used to assess baseline activation of endothelium under homeostatic conditions) did not improve the identification of blood endothelial cells in our analysis.”
§ Structural cells are key regulators of organ-specific immune response > Results > Mapping structural cells across organs
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“The observed patterns were highly organ-specific and seem to modulate the extensive interactions between structural cells and haematopoietic immune cells.”
§ Structural cells are key regulators of organ-specific immune response > Abstract
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In the paper
“In summary, our study uncovered widespread immune gene regulation in structural cells of the mouse, and it established a multi-organ atlas of the underlying epigenetic and transcription-regulatory programs.”
§ Structural cells are key regulators of organ-specific immune response > Abstract
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“We also observed widespread upregulation of interferon-induced as well as interferon-stimulated genes and of key transcriptional regulators in the interferon pathway, which indicates a strong interferon response to LCMV infection in structural cells (Supplementary Table 9).”
§ Structural cells are key regulators of organ-specific immune response > Results > Immune genes induced by viral infection
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“The enrichment analysis provided an initial biological annotation of the identified marker genes (Fig. 1d) and validated their enrichment for previously reported cell-type-specific and organ-specific marker genes expressed in structural cells (Extended Data Fig 3a).”
§ Structural cells are key regulators of organ-specific immune response > Methods > Bioinformatic analysis of cell-type-specific and organ-specific gene expression
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“We observed unexpectedly strong and densely regulated expression of immune genes, both under homeostatic conditions and in response to immunological challenges (systemic viral infection with LCMV, in vivo cytokine treatment).”
§ Structural cells are key regulators of organ-specific immune response > Discussion
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“We detected the strongest association in liver, lung and spleen (Fig. 4b, right).”
§ Structural cells are key regulators of organ-specific immune response > Results > Immune genes induced by viral infection
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“The highest correlation between gene expression and promoter accessibility was observed in brain, caecum, heart, kidney, large intestine and skin, leaving comparatively less room for unrealized epigenetic potential.”
§ Structural cells are key regulators of organ-specific immune response > Results > Epigenetic potential for gene activation
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“The genes that were upregulated in response to systemic LCMV infection showed strong enrichment for immune functions (Fig. 4c), including ‘positive regulation of immune response’, ‘defence response to virus’, ‘cellular response to IFNγ’, and ‘antigen processing and presentation’.”
§ Structural cells are key regulators of organ-specific immune response > Results > Immune genes induced by viral infection
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“We further observed widespread cell-type-specific and organ-specific differences, which were not solely due to differential expression of individual cell surface receptors (Extended Data Fig. 11b), but appear to reflect more general differences in immune gene regulation.”
§ Structural cells are key regulators of organ-specific immune response > Results > Cytokine response of structural cells
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“Third, our integrative analysis of gene expression and chromatin accessibility identified an epigenetically encoded immune potential in structural cells, constituted by genes that were lowly expressed under homeostatic conditions but epigenetically poised for much higher expression.”
§ Structural cells are key regulators of organ-specific immune response > Discussion
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In the paper
“Systemic LCMV infection thus triggered widespread activation of immune genes that were lowly expressed but epigenetically poised under homeostatic conditions.”
§ Structural cells are key regulators of organ-specific immune response > Results > Immune genes induced by viral infection
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In the paper
“We observed an increase in the strength and scope of predicted cell–cell interactions after LCMV infection as compared to homeostatic conditions, largely driven by upregulated gene expression levels for receptors and ligands in structural cells, including B2m, Cd74, Cd47, Cxcl10, Sdc1, Sdc4, Tnfrsf1a and Vcam1.”
§ Structural cells are key regulators of organ-specific immune response > Results > Immune genes induced by viral infection
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“Cytokine administration induced genes involved in metabolic processes (Cmpk2, Pofut2) as well as regulators of vesicle or membrane trafficking and antigen presentation (Bloc1s6, H2-Eb1, Rabac1 and Sar1a) (Fig. 5d, right, Supplementary Table 11).”
§ Structural cells are key regulators of organ-specific immune response > Results > Cytokine response of structural cells
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“By contrast, the correlation was notably lower in liver, lymph node, spleen and thymus, which suggests that structural cells in these organs harbour a more pronounced epigenetic potential for gene activation in response to various stimuli.”
§ Structural cells are key regulators of organ-specific immune response > Results > Epigenetic potential for gene activation
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“In spleen endothelium (highlighted here because of its strong transcriptional response to LCMV infection), treatment with IFNγ and IL-6 explained a sizable proportion of the LCMV-induced changes (Fig. 5c, top left).”
§ Structural cells are key regulators of organ-specific immune response > Results > Cytokine response of structural cells
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“LCMV infection resulted in changes of structural cell composition in most organs (Extended Data Fig. 8c), and we observed differential gene expression in a cell-type-specific and organ-specific manner (Extended Data Fig. 9a, Supplementary Table 9).”
§ Structural cells are key regulators of organ-specific immune response > Results > Immune genes induced by viral infection
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“Scatterplot illustrating the low correlation between the activated epigenetic potential and the measured viral load across cell types and organs.”
§ Structural cells are key regulators of organ-specific immune response > Extended Data
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“For five of the six cytokines (not including IL-3), the upregulated genes showed significant overlap with the genes that carried unrealized epigenetic potential under homeostatic conditions (Fig. 5c, bottom left).”
§ Structural cells are key regulators of organ-specific immune response > Results > Cytokine response of structural cells
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In the paper
“In summary, structural cells responded in cell-type-specific and organ-specific ways to in vivo stimulation with individual cytokines, which allowed us to functionally dissect the effects of systemic LCMV infection and provides further validation of the observed epigenetic potential for immune gene activity in structural cells.”
§ Structural cells are key regulators of organ-specific immune response > Results > Cytokine response of structural cells
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“By contrast, a subset of crucial immune genes (exemplified by Ifngr1) showed high chromatin accessibility in most samples, indicative of a shared core of immune regulation in structural cells.”
§ Structural cells are key regulators of organ-specific immune response > Results > Regulatory networks in structural cells
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“We observed little overlap between the transcriptional response to the cytokines and to LCMV infection (Fig. 5d, top left), while there was still a strong association with the epigenetic potential (Fig. 5d, bottom left).”
§ Structural cells are key regulators of organ-specific immune response > Results > Cytokine response of structural cells
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“We observed widespread activity of these immune gene modules in structural cells, with highly cell-type-specific and organ-specific patterns (Fig. 2c).”
§ Structural cells are key regulators of organ-specific immune response > Results > Immune gene activity in structural cells
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“We observed an increase in the strength and scope of predicted cell–cell interactions after LCMV infection as compared to homeostatic conditions, largely driven by upregulated gene expression levels for receptors and ligands in structural cells, including B2m, Cd74, Cd47, Cxcl10, Sdc1, Sdc4, Tnfrsf1a and Vcam1.”
§ Structural cells are key regulators of organ-specific immune response > Results > Immune genes induced by viral infection
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In the paper
“LCMV infection resulted in changes of structural cell composition in most organs (Extended Data Fig. 8c), and we observed differential gene expression in a cell-type-specific and organ-specific manner (Extended Data Fig. 9a, Supplementary Table 9).”
§ Structural cells are key regulators of organ-specific immune response > Results > Immune genes induced by viral infection
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In the paper
“The genes with unrealized epigenetic potential in structural cells were enriched for immune functions (Fig. 3f, Extended Data Fig. 7b, Supplementary Tables 7 and 8), consistent with our initial hypothesis.”
§ Structural cells are key regulators of organ-specific immune response > Results > Epigenetic potential for gene activation
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In the paper
“We compared the differential gene expression after LCMV infection with the corresponding epigenetic potential of the genes under homeostatic conditions, and genes with unrealized potential were indeed overrepresented among the LCMV-induced genes (Fig. 4b, left).”
§ Structural cells are key regulators of organ-specific immune response > Results > Immune genes induced by viral infection
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In the paper
“Our integrative analysis of chromatin accessibility and gene expression thus identified an epigenetically encoded potential for immune gene activation in structural cells.”
§ Structural cells are key regulators of organ-specific immune response > Results > Epigenetic potential for gene activation
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In the paper
“We observed little overlap between the transcriptional response to the cytokines and to LCMV infection (Fig. 5d, top left), while there was still a strong association with the epigenetic potential (Fig. 5d, bottom left).”
§ Structural cells are key regulators of organ-specific immune response > Results > Cytokine response of structural cells
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In the paper
“First, we observed extensive cell-type-specific and organ-specific regulation of genes that influence the capabilities of structural cells to engage in predicted interactions with haematopoietic immune cells.”
§ Structural cells are key regulators of organ-specific immune response > Discussion
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In the paper
“We also identified groups of transcription factors that were ubiquitously active in structural cells, such as ELF1, ELF3, ETS1, FLI1 and GATA2 (Extended Data Fig. 6e), which may constitute a shared regulatory basis of immune gene activity in structural cells.”
§ Structural cells are key regulators of organ-specific immune response > Results > Regulatory networks in structural cells
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“Consistent with our RNA-seq analysis, the chromatin profiles were globally more similar between different types of structural cells in one organ than among the same cell type across organs (Extended Data Fig. 6a, b).”
§ Structural cells are key regulators of organ-specific immune response > Results > Regulatory networks in structural cells
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“We observed extensive cell-type-specific and organ-specific chromatin regulation at immune gene loci (Fig. 3b).”
§ Structural cells are key regulators of organ-specific immune response > Results > Regulatory networks in structural cells
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“Many key regulators of transcription in structural cells showed cell-type-specific and organ-specific activity (Fig. 3c, Extended Data Fig. 6d, Supplementary Table 6).”
§ Structural cells are key regulators of organ-specific immune response > Results > Regulatory networks in structural cells
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In the paper
“While structural cells were not well covered in this dataset (Extended Data Fig. 5a; Supplementary Table 5), these profiles were sufficient to independently confirm strong and organ-specific activity of immune genes in structural cells (Extended Data Fig. 5b-d).”
§ Structural cells are key regulators of organ-specific immune response > Results > Immune gene activity in structural cells
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In the paper
“The transcriptional response was globally more similar among structural cells of all three types within the same organ than between structural cells of a given type across organs (Extended Data Fig. 9b), consistent with the patterns of similarity that we observed under homeostatic conditions.”
§ Structural cells are key regulators of organ-specific immune response > Results > Immune genes induced by viral infection
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In the paper
“These three cell types, which we refer to as “structural cells”, have been shown to contribute in important ways to mammalian immunity7–11.”
§ Structural cells are key regulators of organ-specific immune response > Abstract
What the sources say
- Not checked yetcites [7] Humbert, M., Hugues, S. & Dubrot, J. Shaping of peripheral T cell responses by lymphatic endothelial cells. Front. Immunol. 7, 684 (2017). source
- Not checked yetcites [8] Malhotra, D., Fletcher, A. L. & Turley, S. J. Stromal and hematopoietic cells in secondary lymphoid organs: partners in immunity. Immunol. Rev. 251, 160–176 (2013). source
- Not checked yetcites [9] Nowarski, R., Jackson, R. & Flavell, R. A. The stromal intervention: Regulation of immunity and inflammation at the epithelial-mesenchymal barrier. Cell 168, 362–375 (2017). source
- Not checked yetcites [10] Perez-Shibayama, C., Gil-Cruz, C. & Ludewig, B. Fibroblastic reticular cells at the nexus of innate and adaptive immune responses. Immunol. Rev. 289, 31–41 (2019). source
- Not checked yetcites [11] Turley, S. J., Cremasco, V. & Astarita, J. L. Immunological hallmarks of stromal cells in the tumour microenvironment. Nat. Rev. Immunol. 15, 669–682 (2015). source
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In the paper
“All assays produced high-quality data (Supplementary Table 1).”
§ Structural cells are key regulators of organ-specific immune response > Results > Mapping structural cells across organs
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In the paper
“Our standardized tissue dissociation did not cause major technical biases (Extended Data Fig. 1d).”
§ Structural cells are key regulators of organ-specific immune response > Results > Mapping structural cells across organs
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In the paper
“Notably, the expression profiles of structural cells within the same organ were globally more similar to each other than structural cells of the same type across organs (Fig. 1d, e, Extended Data Fig. 3d), which suggests that the tissue and organ environment has a major effect on the transcriptomes of structural cells.”
§ Structural cells are key regulators of organ-specific immune response > Results > Mapping structural cells across organs
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In the paper
“The observed patterns were highly organ-specific and seem to modulate the extensive interactions between structural cells and haematopoietic immune cells.”
§ Structural cells are key regulators of organ-specific immune response > Abstract
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In the paper
“Similarly, sorting of fibroblasts as GP38+CD31− cells did not miss any major cell populations identified by the alternative markers CD90.2 (Thy-1.2), LTβR or PDGFRα.”
§ Structural cells are key regulators of organ-specific immune response > Results > Mapping structural cells across organs
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In the paper
“For example, strong expression of collagens (Col4a3, Col4a4, Col5a1, Col6a1, Col12a1) and of complement component 3 (C3) in fibroblasts is expected to enhance their ability to interact with hematopoietic cells; high levels of Muc2 and Arg2 in the digestive tract fosters interactions with macrophages and NK cells; and Ccl25 expression in thymus epithelium contributes to the maturation of T cells.”
§ Structural cells are key regulators of organ-specific immune response > Results > Immune gene activity in structural cells
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In the paper
“To maximize comparability across organs, we developed a standardized workflow for tissue dissociation and cell purification (Fig. 1a).”
§ Structural cells are key regulators of organ-specific immune response > Results > Mapping structural cells across organs
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In the paper
“The cellular identity of the sorted endothelium, epithelium and fibroblasts was further confirmed by RNA-seq data analysis, which showed the expected organ-specific (Extended Data Fig. 3a) and cell-type-specific (Extended Data Fig. 3b) patterns of gene expression compared to published multi-tissue expression profiles18, 19.”
§ Structural cells are key regulators of organ-specific immune response > Results > Mapping structural cells across organs
What the sources say
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In the paper
“Purification of CD31+GP38− endothelial cells specifically enriched for blood endothelium while excluding the less prevalent CD31+GP38+ cells of lymphatic endothelium, which facilitates the comparison across organs.”
§ Structural cells are key regulators of organ-specific immune response > Results > Mapping structural cells across organs
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In the paper
“This epigenetic potential is expected to facilitate the rapid response to immunological challenges in a cell-type-specific and organ-specific manner.”
§ Structural cells are key regulators of organ-specific immune response > Results > Epigenetic potential for gene activation
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In the paper
“The resulting structural cell signatures thus reflect gene expression in one cell type compared to the other cell types in the same organ.”
§ Structural cells are key regulators of organ-specific immune response > Methods > Bioinformatic analysis of cell-type-specific and organ-specific gene expression
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In the paper
“Thus, the administration of cytokines triggered different aspects of the epigenetic potential in liver fibroblasts compared with LCMV infection.”
§ Structural cells are key regulators of organ-specific immune response > Results > Cytokine response of structural cells
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In the paper
“These cytokines thus triggered similar aspects of the epigenetic potential in spleen endothelium as observed for systemic LCMV infection.”
§ Structural cells are key regulators of organ-specific immune response > Results > Cytokine response of structural cells
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In the paper
“We also identified groups of transcription factors that were ubiquitously active in structural cells, such as ELF1, ELF3, ETS1, FLI1 and GATA2 (Extended Data Fig. 6e), which may constitute a shared regulatory basis of immune gene activity in structural cells.”
§ Structural cells are key regulators of organ-specific immune response > Results > Regulatory networks in structural cells
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In the paper
“By contrast, the correlation was notably lower in liver, lymph node, spleen and thymus, which suggests that structural cells in these organs harbour a more pronounced epigenetic potential for gene activation in response to various stimuli.”
§ Structural cells are key regulators of organ-specific immune response > Results > Epigenetic potential for gene activation
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In the paper
“These results support our model of an epigenetically encoded potential for immune gene activation in structural cells in the context of viral infection.”
§ Structural cells are key regulators of organ-specific immune response > Results > Immune genes induced by viral infection
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In the paper
“Given the scale of our study, it was not possible to validate the inferred cell-cell interactions experimentally; however, the identification of many well-established interactions and of biologically plausible differences between cell types and organs provides support for these predictions.”
§ Structural cells are key regulators of organ-specific immune response > Methods > Bioinformatic inference of cell-cell interactions
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In the paper
“While structural cells were not well covered in this dataset (Extended Data Fig. 5a; Supplementary Table 5), these profiles were sufficient to independently confirm strong and organ-specific activity of immune genes in structural cells (Extended Data Fig. 5b-d).”
§ Structural cells are key regulators of organ-specific immune response > Results > Immune gene activity in structural cells
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In the paper
“We further observed widespread cell-type-specific and organ-specific differences, which were not solely due to differential expression of individual cell surface receptors (Extended Data Fig. 11b), but appear to reflect more general differences in immune gene regulation.”
§ Structural cells are key regulators of organ-specific immune response > Results > Cytokine response of structural cells
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In the paper
“We thus conclude that structural cells are epigenetically pre-programmed for a swift response to a variety of immunological challenges.”
§ Structural cells are key regulators of organ-specific immune response > Discussion
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In the paper
“the experimental results do not support an absolute quantification of viral load in each organ”
§ Structural cells are key regulators of organ-specific immune response > Extended Data
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- It may state two separate claims as one. 18
- Probably not a substantial claim. 26
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In the paper
“We also observed the expected expression patterns for various cell-type-specific marker genes, but with a high degree of transcriptional heterogeneity across organs (Extended Data Fig. 3c, Supplementary Table 2).”
§ Structural cells are key regulators of organ-specific immune response > Results > Mapping structural cells across organs
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In the paper
“All three types of structural cells were detectable in all 12 organs, with strong differences in their relative frequencies (Fig. 1b, Extended Data Fig. 1c).”
§ Structural cells are key regulators of organ-specific immune response > Results > Mapping structural cells across organs
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In the paper
“These genes were enriched for immune functions, and they were preferentially upregulated in response to LCMV infection and cytokine administration in vivo.”
§ Structural cells are key regulators of organ-specific immune response > Discussion
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In the paper
“Second, our genome-wide analysis of chromatin accessibility in structural cells uncovered not only a regulatory basis of their immune functions, but also an initial assessment of the transcriptional regulators that confer cellular identity to endothelial cells, epithelial cells and fibroblasts across 12 organs.”
§ Structural cells are key regulators of organ-specific immune response > Discussion
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In the paper
“These organ-specific differences showed no clear correlation with differences in viral load (Extended Data Fig. 9c) and appear to constitute intrinsic regulatory differences between cell types and organs (Extended Data Fig. 9d).”
§ Structural cells are key regulators of organ-specific immune response > Results > Immune genes induced by viral infection
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In the paper
“Together, these data reveal widespread activity of immune genes and regulatory modules in structural cells, which are expected to mediate cell-type-specific and organ-specific interactions with haematopoietic immune cells.”
§ Structural cells are key regulators of organ-specific immune response > Results > Immune gene activity in structural cells
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- Rests on an assumption: Expression of a receptor and its ligand in structural and hematopoietic cells implies potential cell-cell interaction.
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In the paper
“In total, we identified 1,665 genes that fulfilled our definition of unrealized epigenetic potential, of which 335 genes were annotated with at least one immunological term (odds ratio 1.37, P < 10−5, Fisher’s exact test).”
§ Structural cells are key regulators of organ-specific immune response > Results > Epigenetic potential for gene activation
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In the paper
“In conclusion, our study provides a comprehensive characterization of immune gene regulation in structural cells, and an initial step towards the systematic, organism-scale dissection of immune functions beyond haematopoietic cells.”
§ Structural cells are key regulators of organ-specific immune response > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IFN-α treatment had the strongest effect, inducing known interferon target genes and several genes associated with antiviral immunity (Fig. 5b, Extended Data Fig. 10; Supplementary Table 11).”
§ Structural cells are key regulators of organ-specific immune response > Results > Cytokine response of structural cells
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Multi-omics profiling has emerged as a promising approach to dissecting immune regulation in a systematic, genome-wide manner, as illustrated by recent work on the systems immunology of hematopoietic immune cells12, 13.”
§ Structural cells are key regulators of organ-specific immune response > Abstract
What the sources say
- Not checked yetcites [12] Davis, M. M., Tato, C. M. & Furman, D. Systems immunology: just getting started. Nat. Immunol. 18, 725–732 (2017). source
- Not checked yetcites [13] Villani, A. C., Sarkizova, S. & Hacohen, N. Systems immunology: learning the rules of the immune system. Annu. Rev. Immunol. 36, 813–842 (2018). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“However, immune functions are not unique to hematopoietic cells, and many other cell types display basic mechanisms of pathogen defence3–5.”
§ Structural cells are key regulators of organ-specific immune response > Abstract
What the sources say
- Not checked yetcites [3] Buckley, C. D., Barone, F., Nayar, S., Bénézech, C. & Caamaño, J. Stromal cells in chronic inflammation and tertiary lymphoid organ formation. Annu. Rev. Immunol. 33, 715–745 (2015). source
- Not checked yetcites [4] Pober, J. S. & Sessa, W. C. Evolving functions of endothelial cells in inflammation. Nat. Rev. Immunol. 7, 803–815 (2007). source
- Not checked yetcites [5] Schleimer, R. P., Kato, A., Kern, R., Kuperman, D. & Avila, P. C. Epithelium: at the interface of innate and adaptive immune responses. J. Allergy Clin. Immunol. 120, 1279–1284 (2007). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Specific emphasis was put on ensuring high purity of the structural cell transcriptomes, while minimizing the risk and impact of potential contaminations (e.g., due to cell-free RNA released by dying cells or as the result of potential impurities during FACS purification of the structural cell populations).”
§ Structural cells are key regulators of organ-specific immune response > Methods > RNA-seq data processing and quality control
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To avoid biases due to differences in peak size, all regions were standardized to 500 base pairs around the center of the peak.”
§ Structural cells are key regulators of organ-specific immune response > Methods > Bioinformatic analysis of cell-type-specific and organ-specific transcription regulation
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No regulators were excluded based on low or undetectable RNA expression levels, given that transcription factors can play a relevant regulatory role despite low expression levels.”
§ Structural cells are key regulators of organ-specific immune response > Methods > Bioinformatic analysis of cell-type-specific and organ-specific transcription regulation
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Rests on an assumption: Transcription factors can play a relevant regulatory role despite low or undetectable RNA expression levels.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Samples with detectable contamination by hematopoietic immune cells were automatically discarded, and replacement samples were generated until three uncontaminated samples were available for each cell type in each organ.”
§ Structural cells are key regulators of organ-specific immune response > Methods > RNA-seq data processing and quality control
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Finally, we computationally corrected for residual contamination in the retained samples by regressed out epigenomic signatures of hematopoietic immune cells from the matrix of signal intensity values across peaks, using the function removeBatchEffect from the limma package in R.”
§ Structural cells are key regulators of organ-specific immune response > Methods > ATAC-seq and ChIPmentation data processing and quality control
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To make these coarse approximations more robust and interpretable, we used the ATAC-seq data to exclude motifs that are most likely inactive in the investigated cell types.”
§ Structural cells are key regulators of organ-specific immune response > Methods > Bioinformatic analysis of cell-type-specific and organ-specific transcription regulation
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Given the scale of our study, it was not possible to validate the inferred cell-cell interactions experimentally; however, the identification of many well-established interactions and of biologically plausible differences between cell types and organs provides support for these predictions.”
§ Structural cells are key regulators of organ-specific immune response > Methods > Bioinformatic inference of cell-cell interactions
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, structural cells responded in cell-type-specific and organ-specific ways to in vivo stimulation with individual cytokines, which allowed us to functionally dissect the effects of systemic LCMV infection and provides further validation of the observed epigenetic potential for immune gene activity in structural cells.”
§ Structural cells are key regulators of organ-specific immune response > Results > Cytokine response of structural cells
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Low expression with high promoter accessibility indicates an unrealized potential for increased expression.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To detect and remove potential biases arising from contaminating RNA of hematopoietic immune cells among the sorted structural cell populations, we screened all transcriptome profiles for gene expression signatures associated with eight types of hematopoietic immune cells.”
§ Structural cells are key regulators of organ-specific immune response > Methods > RNA-seq data processing and quality control
plaincorrelationaln = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“As an additional precaution, we computationally corrected for residual contamination by RNA from hematopoietic immune cells, regressing out the gene signatures of hematopoietic immune cells from the matrix of structural cell transcriptomes using the function removeBatchEffect from the limma package in R.”
§ Structural cells are key regulators of organ-specific immune response > Methods > RNA-seq data processing and quality control
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We therefore tested multiple surface markers across organs and optimized a sorting scheme that produced consistent results for all 12 investigated organs, while excluding cell types that were detectable only in one or a few tissues (most notably lymphatic endothelial cells).”
§ Structural cells are key regulators of organ-specific immune response > Methods > Standardized sample collection and organ dissociation
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Samples with detectable contamination by hematopoietic immune cells were identified in the same way as for the RNA-seq data, using epigenomic signals in promoter peaks to calculate immune cell signatures.”
§ Structural cells are key regulators of organ-specific immune response > Methods > ATAC-seq and ChIPmentation data processing and quality control
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The results should therefore be regarded as an indication (rather than as a precise quantitative measure) of the degree to which structural cells in different organs are directly and indirectly affected by the LCMV infections.”
§ Structural cells are key regulators of organ-specific immune response > Methods > Quantification of LCMV viral RNA
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No statistical methods were used to predetermine sample size.”
§ Structural cells are key regulators of organ-specific immune response > Methods > Mice
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The RNA-seq data were processed and quality-controlled using established bioinformatics software and custom analysis scripts.”
§ Structural cells are key regulators of organ-specific immune response > Methods > RNA-seq data processing and quality control
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The same digestion solution was used for all organs, to avoid organ-specific technical confounders.”
§ Structural cells are key regulators of organ-specific immune response > Methods > Standardized sample collection and organ dissociation
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Transcriptome profiling by Smart-seq2 was done in three biologically independent experiments.”
§ Structural cells are key regulators of organ-specific immune response > Methods > Transcriptome profiling by Smart-seq2
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All mouse experiments were performed in individually ventilated cages according to the respective animal experiment licenses (BMWFW-66.009/0199-WF/V/3v/2015 and BMWFW-66.009/0361-WF/V/3b/2017) approved by the institutional ethical committees and the institutional guidelines at the Department for Biomedical Research of the Medical University of Vienna.”
§ Structural cells are key regulators of organ-specific immune response > Methods > Mice
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The ATAC-seq and H3K4me2 ChIPmentation data were processed using well-established bioinformatics pipelines, followed by quality control following the same approach as for the RNA-seq data (described above).”
§ Structural cells are key regulators of organ-specific immune response > Methods > ATAC-seq and ChIPmentation data processing and quality control
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The experiments were not randomized, and investigators were not blinded to treatment status during experiments and outcome assessment.”
§ Structural cells are key regulators of organ-specific immune response > Methods > Mice
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our gene expression analysis likely reflects a superposition of several such effects.”
§ Structural cells are key regulators of organ-specific immune response > Methods > Bioinformatic analysis of the LCMV infection experiments
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- The authors state this as an assumption: LCMV infection, a systemic infection model, affects structural cells in most or all investigated organs through direct effects (structural cells may get infected) and indirect effects (structural cells respond to aspects of tissue-specific and systemic infection).
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Importantly, this qPCR assay estimates infection levels based on LCMV viral RNA in bulk tissue, and it cannot account for organ-specific differences in the relative frequencies of cells that are susceptible to LCMV infection.”
§ Structural cells are key regulators of organ-specific immune response > Methods > Quantification of LCMV viral RNA
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The experimental workflow followed the recommendations of the Immunological Genome Project34 regarding sample collection schedule, antibody staining, and sample pooling.”
§ Structural cells are key regulators of organ-specific immune response > Methods > Standardized sample collection and organ dissociation
What the sources say
- Not checked yetcites [34] ImmGen Consortium. Final ImmGen sorting SOP; http://www.immgen.org/Protocols/ImmGen%20Cell%20prep%20and%20sorting%20SOP.pdf (accessed 24 March 2020).
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our inferred gene-regulatory networks support a model in which constitutively active regulators establish a shared core of immune functions, while additional factors contribute cell-type-specific and organ-specific adaptions.”
§ Structural cells are key regulators of organ-specific immune response > Results > Regulatory networks in structural cells
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Contaminated samples were automatically removed and replaced by new samples.”
§ Structural cells are key regulators of organ-specific immune response > Methods > ATAC-seq and ChIPmentation data processing and quality control
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Epigenome mapping by ChIPmentation was done in two biologically independent experiments, with two exceptions: for endothelium from lymph node and fibroblasts from thymus, only one high-quality profile could be obtained).”
§ Structural cells are key regulators of organ-specific immune response > Methods > Epigenome mapping by ChIPmentation for H3K4me2
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“nor do they account for differences in the relative frequencies of cells that are susceptible to LCMV infection in each organ”
§ Structural cells are key regulators of organ-specific immune response > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Chromatin accessibility mapping by ATAC-seq was done in two biologically independent experiments.”
§ Structural cells are key regulators of organ-specific immune response > Methods > Chromatin accessibility mapping by ATAC-seq
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
There has been little systematic investigation of structural cells across organs.
“However, there has been little systematic investigation across organs, in part because structural cells are difficult to study by genetic ablation due to their essential structural roles in most organs.”
“However, comparative multi-organ investigations of structural cells have been lacking.”
The paper relies on this without support.
Structural cells are difficult to study by genetic ablation due to their essential structural roles in most organs.
“However, there has been little systematic investigation across organs, in part because structural cells are difficult to study by genetic ablation due to their essential structural roles in most organs.”
The paper relies on this without support.
Expression of a receptor and its ligand in structural and hematopoietic cells implies potential cell-cell interaction.
“by inferring a network of potential cell–cell interactions based on known receptor–ligand pairs”
“The resulting cell–cell interaction network (Fig. 2a, Supplementary Table 3) predicted frequent crosstalk between structural cells and haematopoietic cells under homeostasis (Fig. 2a, Extended Data Fig. 4a).”
The paper relies on this without support.
Low expression with high promoter accessibility indicates an unrealized potential for increased expression.
“We then scanned for genes with low expression but high promoter accessibility, indicative of an unrealized potential for increased expression (Fig. 3d, e, Extended Data Fig. 7a).”
“In total, we identified 1,665 genes that fulfilled our definition of unrealized epigenetic potential, of which 335 genes were annotated with at least one immunological term (odds ratio 1.37, P < 10−5, Fisher’s exact test).”
The paper relies on this without support.
The correlation between gene expression and promoter accessibility can be used to quantify epigenetic potential across cell types and organs.
“To quantify and compare the epigenetic potential across cell types and organs (Fig. 3g), we exploited that genes with strong unrealized potential are outliers when plotting gene expression against promoter accessibility, which results in a reduced correlation between the two data types (Extended Data Fig. 7a).”
The authors state this as an assumption.
LCMV infection, a systemic infection model, affects structural cells in most or all investigated organs through direct effects (structural cells may get infected) and indirect effects (structural cells respond to aspects of tissue-specific and systemic infection).
“This analysis was based on the hypothesis that LCMV infection – which is widely regarded as a systemic infection model – will affect structural cells in most or all investigated organs through direct effects (structural cells may get infected) as well as indirect effects (structural cells respond to aspects of tissue-specific and systemic infection).”
The paper relies on this without support.
Transcription factors can play a relevant regulatory role despite low or undetectable RNA expression levels.
“No regulators were excluded based on low or undetectable RNA expression levels, given that transcription factors can play a relevant regulatory role despite low expression levels.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Several interactions were predicted across all ventricles and ages, between immune cells and structural cells (epithelial, mesenchymal and endothelial), in line with the diverse functions assigned to immune cells in other barrier systems (Krausgruber et al., 2020).”
From A cellular and spatial map of the choroid plexus across brain ventricles and ages (2021) · cites this paper as Krausgruber et al., 2020
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Structural cells are key regulators of organ-specific immune response > Methods > Epigenome mapping by ChIPmentation for H3K4me2
“Final enrichment of the libraries was performed in a 50 μl reaction”
§ Structural cells are key regulators of organ-specific immune response > Methods > Epigenome mapping by ChIPmentation for H3K4me2
“25 ml Kapa HiFi HotStart ReadyMix.”
Citations
Cites
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Full-length RNA-seq from single cells using Smart-seq2
Picelli, S., Faridani, O. R., Björklund, Å. K., Winberg, G., Sagasser, S., & Sandberg, R. (2014) · Nature Protocols · doi:10.1038/nprot.2014.006 · Cited by 4,137
A gene atlas of the mouse and human protein-encoding transcriptomes
Su, A. I., Wiltshire, T., Batalov, S., Lapp, H., Ching, K. A., Block, D., Zhang, J., Soden, R., Hayakawa, M., Kreiman, G., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0400782101 · Cited by 3,475
Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris
The Tabula Muris Consortium, coordination, O., coordination, L., processing, O. C. A., sequencing, L. P. A., analysis, C. D., annotation, C. T., Writing group, Supplemental text writing group, & Principal investigators (2018) · Nature · doi:10.1038/s41586-018-0590-4 · Cited by 2,842
Single-cell reconstruction of the early maternal–fetal interface in humans
Vento-Tormo, R., Efremova, M., Botting, R. A., Turco, M. Y., Vento-Tormo, M., Meyer, K. B., Park, J.-E., Stephenson, E., Polański, K., Goncalves, A., et al. (2018) · Nature · doi:10.1038/s41586-018-0698-6 · Cited by 2,358
Tissue-Resident Macrophage Enhancer Landscapes Are Shaped by the Local Microenvironment
Lavin, Y., Winter, D., Blecher-Gonen, R., David, E., Keren-Shaul, H., Merad, M., Jung, S., & Amit, I. (2014) · Cell · doi:10.1016/j.cell.2014.11.018 · Cited by 2,167
Evolving functions of endothelial cells in inflammation
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A single-cell survey of the small intestinal epithelium
Haber, A. L., Biton, M., Rogel, N., Herbst, R. H., Shekhar, K., Smillie, C., Burgin, G., Delorey, T. M., Howitt, M. R., Katz, Y., et al. (2017) · Nature · doi:10.1038/nature24489 · Cited by 1,750
Mapping the Mouse Cell Atlas by Microwell-Seq
Han, X., Wang, R., Zhou, Y., Fei, L., Sun, H., Lai, S., Saadatpour, A., Zhou, Z., Chen, H., Ye, F., et al. (2018) · Cell · doi:10.1016/j.cell.2018.02.001 · Cited by 1,597
Homeostasis, Inflammation, and Disease Susceptibility
Kotas, M. E., & Medzhitov, R. (2015) · Cell · doi:10.1016/j.cell.2015.02.010 · Cited by 1,213
Research works printed but not linked: 2
- Abbas, A. K., Lichtman, A. H. & Pillai, S. Cellular and Molecular Immunology 9th edn (Elsevier, 2017).
- Pawlina, W. & Ross, M. H. Histology: a Text and Atlas, International Edition: with Correlated Cell and Molecular Biology (Wolters Kluwer Law & Business, 2019).
Cited by
Sorted by citations
The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth
de Visser, K. E., & Joyce, J. A. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.02.016 · Cited by 4,059
Deciphering cell–cell interactions and communication from gene expression
Armingol, E., Officer, A., Harismendy, O., & Lewis, N. E. (2021) · Nature Reviews Genetics · doi:10.1038/s41576-020-00292-x · Cited by 1,267
Cross-tissue organization of the fibroblast lineage
Buechler, M. B., Pradhan, R., Krishnamurty, A. T., Cox, C. B., Calviello, A. K., Wang, A. W., Yang, Y. A., Tam, L., Caothien, R. H., Roose‐Girma, M., et al. (2021) · Nature · doi:10.1038/s41586-021-03549-5 · Cited by 1,100
Functional characterization of the dural sinuses as a neuroimmune interface
Rustenhoven, J., Drieu, A., Mamuladze, T., de Lima, K. A., Dykstra, T., Wall, M., Papadopoulos, Z., Kanamori, M., Salvador, A. F., Baker, W., et al. (2021) · Cell · doi:10.1016/j.cell.2020.12.040 · Cited by 685
Fibroblasts as immune regulators in infection, inflammation and cancer
Davidson, S., Coles, M. C., Thomas, T. R., Kollias, G. A., Ludewig, B., Turley, S. J., Brenner, M. B., & Buckley, C. D. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-021-00540-z · Cited by 639
Metadata
- Authors
- Krausgruber, T., Fortelny, N., Fife-Gernedl, V., Senekowitsch, M., Schuster, L. C., Lercher, A., Nemc, A., Schmidl, C., Rendeiro, A. F., Bergthaler, A., & Bock, C.
- Affiliations
- Austrian Academy of Sciences (AT)
- Corresponding author
- Bock, Christoph
- ORCID
- Venue
- Nature
- Published
- 2020-07-01
- Volume
- 583
- Issue
- 7815
- Pages
- 296-302
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7610345
- OpenAlex
- W3038974679
- Semantic Scholar
- fa9e61acc18c1bab6a4dd7d909097c9b875eb4ac
- Cited by
- 434
- References
- 44
- Citations by year
- 2026: 39 · 2025: 79 · 2024: 64 · 2023: 63 · 2022: 81 · 2021: 90 · 2020: 18
- FWCI
- 20.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- structural cells, epithelium, endothelium, fibroblasts, immune gene regulation, epigenetic regulation, chromatin accessibility, tissue homeostasis, viral infection, mouse organs
- MeSH terms
- Epigenome, Animals, Chromatin, Endothelium, Epithelial Cells, Female, Fibroblasts, Gene Expression Regulation, Hematopoietic Stem Cells, Immune System, Immunity, Innate, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, Male, Organ Specificity, Transcription, Genetic, Epigenesis, Genetic, Mice, Gene Regulatory Networks, Adaptive Immunity, Transcriptome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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