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This in an interactive tool to explore CD4+ T cell and MSC subpopulations during helminth infection. For more details, please see our publication ....

Reciprocal regulation of Th2 and stroma cells remodels mesenteric adipose tissue in type 2 inflammation


Agnieszka M. Kabat1, Alexandra Hackl1,*, David E. Sanin1,*, Patrice Zeis1,2,3,*, Katarzyna M. Grzes1, Francesc Baixauli1, Ryan Kyle11, George Caputa1, Joy Edwards-Hicks1, Matteo Villa1, Nisha Rana1, Jonathan D. Curtis1, Angela Castoldi1, Jovana Cupovic1, Leentje Dreesen4, J. Andrew Pospisilik5, Joseph F. Urban Jr6, Dominic Grün1,7, Erika L. Pearce1,8,9, Edward J. Pearce1,3,8,10,**
1Max Planck Institute for Immunobiology and Epigenetics, Freiburg 79108, Germany
2International Max Planck Research School for Molecular and Cellular Biology (IMPRS-MCB), Freiburg, Germany
3Faculty of Biology, University of Freiburg, Freiburg 79104, Germany
4Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
5Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
6USDA, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet, Genomics, and Immunology Laboratory, Beltsville, MD 20705, USA
7CIBSS-Centre for Integrative Biological Signaling Studies, University of Freiburg, Freiburg 79104, Germany
8Bloomberg Kimmel Institute, and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
9Department of Biochemistry and Molecular Biology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
10Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
*equal contribution
**correspondong author: epearce7@jhmi.edu

Summary

Adipose tissue (AT) contains mesenchymal stromal cells (MSC) in stages of commitment to becoming specialized tissue cells, including adipocytes and fibroblasts, and immune cells which support tissue homeostasis. How MSC and immune cells interact during infection is poorly understood. We show that during intestinal helminth infection MSC in mesenteric AT (mAT) become enriched in non-differentiated progenitor cells. This is accompanied by MSC-intrinsic metabolic reprogramming supporting increased secretion of extracellular matrix (ECM), IL-33, and TSLP. In parallel, Th2 resident memory (Th2RM) cells populate the mAT and persist after infection is resolved. These cells express Areg, TGFβ and IL-5, and are necessary to promote infection induced changes within mAT, including MSC reprogramming and tissue eosinophilia. In turn, IL-33 and TSLP from MSC facilitate Th2RM activation and maintenance. Our findings link Th2RM cells to mAT remodeling during intestinal infection, underscoring the reciprocal dependence of stroma and resident immune cells for lasting tissue immunity.



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CD4+ T cell dataset

To explore the biology of mAT Th2 cells in comparison to Th2 cells from the mLN and the small intestine lamina propria (SI) during the H. polygyrus-induced response scRNA-seq was performed using sorted CD4+ TCRβ+ T cells from mice during primary infection and, where possible, secondary infection (re-infection), with uninfected mice as a reference control. Clustering analysis revealed distinct groupings of T cell populations by tissue of residence.

CD4+ T cells

CD4+ T cell Cluster Composition(normalised)

UMAP representations indicating log2 normalized(left) or normalized expression(right) of selected genes.

log2 norm. expression

norm. expression

FractionDotPlot for Clusters

Cluster-specific gene expression shown as fractiondotplots. Colour represents the Z score of the mean expression(left) or log2 normalized expression(right) across clusters and dot size represents the fraction of cells in the cluster expressing the selected gene. For expression color code, log2 mean expression above for 4 or below -4 are replaced by 4 and -4, respectively. Z scores above 1 and -1 are replaced by 1 and -1, respectively
Z score of mean expression
log2 mean expression

FractionDotPlot for Samples

Sample-specific gene expression shown as fractiondotplots. Colour represents the Z score of the mean expression(left) or log2 normalized expression(right) across samples and dot size represents the fraction of cells in the sample expressing the selected gene. For expression color code, log2 mean expression above for 4 or below -4 are replaced by 4 and -4, respectively. Z scores above 1 and -1 are replaced by 1 and -1, respectively
Z score of mean expression
log2 mean expression

Differential Expression Cluster1 against Cluster2




Differential Expression Cluster versus all other

mean.cl = mean expression within cluster, mean.other.cl = mean expression in all other cluster, log2FC = log2 Foldchange selected clusters versus all other

pval = p-value, padj = adjusted p-value



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MSC data

To explore mAT MSC cell biology during helminth infection scRNA-seq was performed on MSC cells sorted from mice during primary infection, secondary infection and uninfected mice as a reference control.

MSCs

MSC Cluster Composition(normalised)

UMAP representations indicating log2 counts (left) or raw counts (right) of selected genes.

log2 expression

expression

FractionDotPlot for Clusters

Cluster-specific gene expression shown as fractiondotplots. Colour represents the Z score of the mean expression(left) or log2 expression(right) across clusters and dot size represents the fraction of cells in the cluster expressing the selected gene. For expression color code, log2 mean expression above for 4 or below -4 are replaced by 4 and -4, respectively. Z scores above 1 and -1 are replaced by 1 and -1, respectively
Z score of mean expression
log2 mean expression

FractionDotPlot for Samples

Sample-specific gene expression shown as fractiondotplots. Colour represents the Z score of the mean expression(left) or log2 nornalized expression(right) across samples and dot size represents the fraction of cells in the sample expressing the selected gene. For expression color code, log2 mean expression above for 4 or below -4 are replaced by 4 and -4, respectively. Z scores above 1 and -1 are replaced by 1 and -1, respectively
Z score of mean expression
log2 mean expression

Differential Expression Cluster1 against Cluster2




Differential Expression Cluster versus all other

mean.cl = mean expression within cluster, mean.other.cl = mean expression in all other cluster, log2FC = log2 Foldchange selected clusters versus all other

pval = p-value, padj = adjusted p-value