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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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Written from the paper’s full text.
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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Claims the paper makes
62 Own result · 31 Own method · 16 Own interpretation · 5 Not checked yet
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
“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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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
“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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In the paper
“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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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.
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
“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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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
“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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In the paper
“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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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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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
“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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- 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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- Rests on an assumption: Low expression with high promoter accessibility indicates an unrealized potential for increased expression.
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
“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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: Expression of a receptor and its ligand in structural and hematopoietic cells implies potential cell-cell interaction.
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
“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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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.
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
“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
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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
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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
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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
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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
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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
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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
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- Rests on an assumption: Transcription factors can play a relevant regulatory role despite low or undetectable RNA expression levels.
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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
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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
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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
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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
“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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- 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
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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
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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
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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
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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
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In the paper
“No statistical methods were used to predetermine sample size.”
§ Structural cells are key regulators of organ-specific immune response > Methods > Mice
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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
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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
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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
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- 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
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Post-transcriptional checkpoints in autoimmunity
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Acute response to pathogens in the early human placenta at single-cell resolution
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Understanding T cell aging to improve anti-viral immunity
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Aldh1a2 + fibroblastic reticular cells regulate lymphocyte recruitment in omental milky spots
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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
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