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Early Life Programming of Mesenteric Lymph Node Stromal Cell Identity by the Lymphotoxin Pathway Regulates Mucosal Immune Responses in the Adult

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE138457 | GEO | 2019/10/05

REPOSITORIES: GEO

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Early Life Programming of Mesenteric Lymph Node Stromal Cell Identity by the Lymphotoxin Pathway Regulates Mucosal Immune Responses in the Adult (Stromal cells)

Project description:Redundant mechanisms support IgA responses to intestinal antigens. These include multiple priming sites (mesenteric lymph nodes (MLN), Peyer's patches and isolated lymphoid follicles) and various cytokines that promote class switch to IgA, even in the absence of T cells. In spite of these back-up mechanisms, vaccination against enteric pathogens such as Rotavirus has limited success in some populations.Genetic and environmental signals experienced during early life are known to influence mucosal immunity, yet the mechanisms for how these exposures operate remain unclear. Here we used Rotavirus infection to follow antigen-specific IgA responses through time and in different gut compartments. Using genetic and pharmacological approaches, we tested the role of a pathway known to support IgA responses (Lymphotoxin - LT) at different developmental stages. We found that LT-beta receptor (LTβR) signalling in early life programs intestinal IgA responses in adulthood by affecting antibody class switch recombination to IgA and subsequent generation of IgA antibody-secreting cells within an intact MLN. In addition, early life LTβR signalling dictates the phenotype and function of MLN stromal cells in order to support IgA responses in the adult. Collectively, our studies uncover new mechanistic insights into how early life LTβR signalling impacts mucosal immune responses during adulthood.

2019-10-05 | GSE138456 | GEO

Early Life Programming of Mesenteric Lymph Node Stromal Cell Identity by the Lymphotoxin Pathway Regulates Mucosal Immune Responses in the Adult (B cells)

2019-10-05 | GSE138455 | GEO

Early Life Programming of Mesenteric Lymph Node Stromal Cell Identity by the Lymphotoxin Pathway Regulates Mucosal Immune Responses in the Adult

Project description:Early Life Programming of Mesenteric Lymph Node Stromal Cell Identity by the Lymphotoxin Pathway Regulates Mucosal Immune Responses in the Adult

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Early Life Programming of Mesenteric Lymph Node Stromal Cell Identity by the Lymphotoxin Pathway Regulates Mucosal Immune Responses in the Adult (Stromal cells)

Project description:Early Life Programming of Mesenteric Lymph Node Stromal Cell Identity by the Lymphotoxin Pathway Regulates Mucosal Immune Responses in the Adult (Stromal cells)

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Early Life Programming of Mesenteric Lymph Node Stromal Cell Identity by the Lymphotoxin Pathway Regulates Mucosal Immune Responses in the Adult (B cells)

Project description:Early Life Programming of Mesenteric Lymph Node Stromal Cell Identity by the Lymphotoxin Pathway Regulates Mucosal Immune Responses in the Adult (B cells)

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Postnatal expansion of mesenteric lymph node stromal cells towards reticular and CD34<sup>+</sup> stromal cell subsets.

Project description: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.

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Lymphotoxin-β receptor signaling through NF-κB2-RelB pathway reprograms adipocyte precursors as lymph node stromal cells.

Project description:Lymph node development during embryogenesis involves lymphotoxin-β receptor engagement and subsequent differentiation of a poorly defined population of mesenchymal cells into lymphoid tissue organizer cells. Here, we showed that embryonic mesenchymal cells with characteristics of adipocyte precursors present in the microenvironment of lymph nodes gave rise to lymph node organizer cells. Signaling through the lymphotoxin-β receptor controlled the fate of adipocyte precursor cells by blocking adipogenesis and instead promoting lymphoid tissue stromal cell differentiation. This effect involved activation of the NF-κB2-RelB signaling pathway and inhibition of the expression of the key adipogenic factors Pparγ and Cebpα. In vivo organogenesis assays show that embryonic and adult adipocyte precursor cells can migrate into newborn lymph nodes and differentiate into a variety of lymph node stromal cells. Thus, we propose that adipose tissues act as a source of lymphoid stroma for lymph nodes and other lymphoid structures associated with fat.

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Stromal mesenteric lymph node cells are essential for the generation of gut-homing T cells in vivo.

Project description:T cells primed in the gut-draining mesenteric lymph nodes (mLN) are imprinted to express alpha4beta7-integrin and chemokine receptor CCR9, thereby enabling lymphocytes to migrate to the small intestine. In vitro activation by intestinal dendritic cells (DC) or addition of retinoic acid (RA) is sufficient to instruct expression of these gut-homing molecules. We report that in vivo stroma cells, but not DC, allow the mLN to induce the generation of gut tropism. Peripheral LN (pLN) transplanted into the gut mesenteries fail to support the generation of gut-homing T cells, even though gut-derived DC enter the transplants and prime T cells. DC that fail to induce alpha4beta7-integrin and CCR9 in vitro readily induce these factors in vivo upon injection into mLN afferent lymphatics. Moreover, uniquely mesenteric but not pLN stroma cells express high levels of RA-producing enzymes and support induction of CCR9 on activated T cells in vitro. These results demonstrate a hitherto unrecognized contribution of stromal cell delivered signals, including RA, on the imprinting of tissue tropism in vivo.

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