Reciprocal regulation of Th2 and stroma cells remodels mesenteric adipose tissue in type 2 inflammation
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ABSTRACT:
PROVIDER: PRJNA772755 | ENA |
REPOSITORIES: ENA
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Project description: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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2022-05-20 | PXD029979 | Pride
Project description:RASA3 regulates the balance of pTh17-Th2 reciprocal programs.
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Project description:Total RNAof pTh17 cells from wild type (WT) and RASA3 KO (RASA3KO) mouse (C57BL/6) was extracted and RNA-seq libraries were generated. Reads (32-45 Million reads per sample) were analyzed with Salmon software to align and quantify the transcript expression. R packages in Bioconductor, tximport and tximportData were used to aggregate transcript-level quantifications to the gene level, with the R package biomaRt for gene and transcripts mapping. The option "lengthScaledTPM" for countsFromAbundance in tximport was used to obtain the estimated counts at the gene level using abundance estimates scaled based on the average transcript length over samples and the library size. R function voom in limma package was used to transform the estimated count data into log2 scale and estimate the mean-variance relationship so that it can be used to compute appropriate observation level weights, followed by linear modelling. For gene-level differential expression analysis, a linear model was fitted to the log scaled expression data with the genotypes (knockout and wild-type) as one covariate using empirical Bayes moderated t-statistics. The false discovery rate (FDR) was controlled using the Benjamini and Hochberg algorithm. Probes with FDR < 0.05 and fold-change > 2 were judged to be differentially expressed. 317 and 35 genes were identified to be significantly up- and down-regulated respectively. The R function CAMERA was used to determine whether each gene set was differentially expressed in the comparisons as a set. The differential expression patterns and to calculate the enrichment scores of Th1/Th2 (KEGG mmu04658) and Th17 (KEGG mmu04659) related genes in the knockout vs. wild-type comparisons. Our analysis demonstrated that increase of Th2 program and decrease Th17 program in RASA3 KO pTh17 cells, with no change of Th1 related genes. This study indicated that RASA3 is vital for the balance of pTh17-Th2 reciprocal programs.
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Project description:Transcriptional profiling of primary human mesenteric adipose-derived stroma cells isolated from control, cancer, Crohn's disease, Ulcerative colitis, and obese patients
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Project description:Th2 cells provide effector functions in type 2 immune responses to helminths and allergens. Despite substantial knowledge about molecular mechanisms of Th2 cell differentiation, there is little information on Th2 cell heterogeneity and clonal distribution between organs mainly due to technical limitations. To address this issue, we performed combined single-cell transcriptome and TCR clonotype analysis on murine Th2 cells in mesenteric lymph nodes (MLN) and lung after infection with Nippostrongylus brasiliensis (Nb) as a model of human hookworm infection. We identified strong organ-specific expression profiles, but also found populations with conserved effector or migration signatures. A substantial MLN subpopulation with an interferon response signature suggests a role for interferon-signaling in Th2 cell differentiation or diversification. RNA-inferred developmental directions further implied proliferation as a hub for differentiation decisions. Although the TCR repertoire appeared to be highly heterogeneous, we identified expanded Th2 clones and CDR3 motifs. Clonal relatedness between distant organs confirmed the effective exchange of Th2 effector cells. However, locally expanded clones dominated the response, as the most expanded clones in MLN and lung did not overlap. This new insight in Th2 cell subsets and clonal relatedness in distant organs demonstrates their heterogeneity and suggests that they serve distinct effector functions.
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2019-09-05 | GSE136883 | GEO
Project description:In addition to adipocytes, adipose tissue (AT) is populated by mesenchymal stem cells (MSC) in stages of commitment to the adipocyte lineage, and immune cells which support homeostatic tissue function. How MSC and immune cells interact during infection is poorly understood. We found that during intestinal nematode infection, MSC in gut-associated AT (mFAT) exhibit a bias away from commitment to the adipocyte lineage towards a pluripotent progenitor state. During this time, MSC became metabolically active, and began secreting the alarmins IL-33 and TSLP, and extracellular matrix collagens. In parallel, mFAT became irreversibly populated by Th2 resident memory (Th2RM) cells, which make the tissue modulatory cytokines amphiregulin and TGFβ1. Secretion of these cytokines, and Th2RM activation and maintenance, was driven by IL-33 and TSLP and in turn MSC activation was induced by amphiregulin and TGFβ1. Our findings link Th2RM cells to reversible mFAT remodeling during intestinal infection and underscore the reciprocal dependence of stroma and resident immune cells for lasting tissue immunity.
2022-10-13 | GSE215137 | GEO
Project description:In addition to adipocytes, adipose tissue (AT) is populated by mesenchymal stem cells (MSC) in stages of commitment to the adipocyte lineage, and immune cells which support homeostatic tissue function. How MSC and immune cells interact during infection is poorly understood. We found that during intestinal nematode infection, MSC in gut-associated AT (mFAT) exhibit a bias away from commitment to the adipocyte lineage towards a pluripotent progenitor state. During this time, MSC became metabolically active, and began secreting the alarmins IL-33 and TSLP, and extracellular matrix collagens. In parallel, mFAT became irreversibly populated by Th2 resident memory (Th2RM) cells, which make the tissue modulatory cytokines amphiregulin and TGFβ1. Secretion of these cytokines, and Th2RM activation and maintenance, was driven by IL-33 and TSLP and in turn MSC activation was induced by amphiregulin and TGFβ1. Our findings link Th2RM cells to reversible mFAT remodeling during intestinal infection and underscore the reciprocal dependence of stroma and resident immune cells for lasting tissue immunity.
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