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Postnatal expansion of the lymph node stromal cell pool towards reticular and CD34+ stromal cell subsets [WGBS]

ABSTRACT: Gut-draining mesenteric lymph nodes (mLNs) provide the framework to shape intestinal adaptive immune responses. We previously delineated transcriptional signatures in LN stromal cells (SC), pointing to tissue-specific variability in SC composition and immunomodulatory function. Here, using scRNA-seq we dissected the developmental trajectory of SCs within mLNs derived from postnatal to aged mice, and identified two putative progenitors, namely CD34+ SC and fibroblastic reticular stromal cell (FRC) progenitors, which both feed the rapid LN expansion postnatally. We further unraveled the tissue-specific chromatin accessibility and DNA methylation landscape of non-endothelial SCs, and identified a microbiota-independent core epigenomic signature, showcasing differences between SCs from mLN and skin-draining peripheral LN. Irf3 was inferred from the epigenomic landscape of SCs, being dynamically expressed along the differentiation trajectories of FRCs. Lentiviral overexpression of Irf3 in a mesenchymal stem cell line established a Cxcl9+ FRC molecular phenotype. The relevance of Irf3 for SC biology was further underscored by the diminished proportion of Ccl19+ and Cxcl9+ FRCs in LNs from Irf3-/- mice. Together, our data constitute a comprehensive transcriptional and epigenomic map of LNSC development in early life and dissect location-specific, microbiota-independent properties of non-endothelial SCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE171905 | GEO | 2022/10/07

REPOSITORIES: GEO

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Postnatal expansion of the lymph node stromal cell pool towards reticular and CD34+ stromal cell subsets [scRNA-seq]

Project description:Gut-draining mesenteric lymph nodes (mLNs) provide the framework to shape intestinal adaptive immune responses. We previously delineated transcriptional signatures in LN stromal cells (SC), pointing to tissue-specific variability in SC composition and immunomodulatory function. Here, using scRNA-seq we dissected the developmental trajectory of SCs within mLNs derived from postnatal to aged mice, and identified two putative progenitors, namely CD34+ SC and fibroblastic reticular stromal cell (FRC) progenitors, which both feed the rapid LN expansion postnatally. We further unraveled the tissue-specific chromatin accessibility and DNA methylation landscape of non-endothelial SCs, and identified a microbiota-independent core epigenomic signature, showcasing differences between SCs from mLN and skin-draining peripheral LN. Irf3 was inferred from the epigenomic landscape of SCs, being dynamically expressed along the differentiation trajectories of FRCs. Lentiviral overexpression of Irf3 in a mesenchymal stem cell line established a Cxcl9+ FRC molecular phenotype. The relevance of Irf3 for SC biology was further underscored by the diminished proportion of Ccl19+ and Cxcl9+ FRCs in LNs from Irf3-/- mice. Together, our data constitute a comprehensive transcriptional and epigenomic map of LNSC development in early life and dissect location-specific, microbiota-independent properties of non-endothelial SCs.

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