Postnatal expansion of mesenteric lymph node stromal cells towards reticular and CD34+ stromal cell subsets

Abstract

Gut-draining mesenteric lymph nodes (LN) provide the framework to shape intestinal adaptive immune responses. Based on the transcriptional signatures established by our previous work, the composition and immunomodulatory function of LN stromal cells (SC) vary according to location. Here, we describe the single-cell composition and development of the SC compartment within mesenteric LNs derived from postnatal to aged mice. We identify CD34+ SC and fibroblastic reticular stromal cell (FRC) progenitors as putative progenitors, both supplying the typical rapid postnatal mesenteric LN expansion. We further establish the location-specific chromatin accessibility and DNA methylation landscape of non-endothelial SCs and identify a microbiota-independent core epigenomic signature, showing characteristic differences between SCs from mesenteric and skin-draining peripheral LNs. The epigenomic landscape of SCs points to dynamic expression of Irf3 along the differentiation trajectories of FRCs. Accordingly, a mesenchymal stem cell line acquires a Cxcl9+ FRC molecular phenotype upon lentiviral overexpression of Irf3, and the relevance of Irf3 for SC biology is further underscored by the diminished proportion of Ccl19+ and Cxcl9+ FRCs in LNs of Irf3-/- mice. Together, our data constitute a comprehensive transcriptional and epigenomic map of mesenteric LNSC development in early life and dissect location-specific, microbiota-independent properties of non-endothelial SCs.

Fibroblastic reticular cells provide a supportive niche for lymph node–resident macrophages

“…Characterisation of clusters was based on the expression of a combination of known marker genes and expression pattern of unbiased calculated marker genes. This approach is important as the expression pattern of single genes can vary between tissue site and cellular state, even between LNs from distinct sampling sites ([ 54 , 55 ]). This can only be resolved by cross‐organ studies that will identify more conserved marker genes in the future.…”

Lymph node stromal cell responses to perinatal T cell waves, a temporal atlas

“…Likewise, ontogenetic differences between hematopoietic cell progenitors from the fetal liver versus bone marrow may explain variations in epigenetic profiles and differentiation potentials in perinates versus adults ( 20 – 22 ). Once they emerge from the thymus, perinatal T cells are confronted with a distinct environment in secondary lymphoid organs or within a diversity of nonlymphoid tissues, which may predicate differential priming, proliferation, or cellular cross talk vis-a-vis newly emergent adult T cells ( 23 – 26 ).…”