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Aldh1a2+ fibroblastic reticular cells regulate lymphocyte recruitment in omental milky spots

ABSTRACT: Milky spots, lymphoid clusters present in visceral adipose tissue omentum, play central roles in the regulation of abdominal immunity. Milky spots exhibit hybrid nature between secondary lymph organs and ectopic lymphoid tissues, yet the mechanism of their development and maturation is poorly understood. Here, we identified a subset of fibroblastic reticular cells (FRCs) that are uniquely present in omental milky spots. These FRCs were characterized by the expression of retinoic acid converting enzyme, Aldh1a2, and endothelial cell marker, Tie2, in addition to canonical FRC-associated genes. Diphtheria toxin-mediated ablation of Aldh1a2+ FRCs resulted in the alteration in milky spot structure with a significant reduction in size and cellularity. Mechanistically, Aldh1a2+ FRCs regulated the display of chemokine CXCL12 on high endothelial venules (HEVs), which recruit blood-borne lymphocytes from circulation. We further found that Aldh1a2+ FRCs are required for the maintenance of peritoneal lymphocyte composition. These results illustrate the homeostatic roles of FRCs in the formation of non-classical lymphoid tissues.

ORGANISM(S): Mus musculus

PROVIDER: GSE224023 | GEO | 2023/02/14

REPOSITORIES: GEO

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Aldh1a2+ fibroblastic reticular cells regulate lymphocyte recruitment in omental milky spots (single cell RNA-Seq)

Project description:Milky spots, lymphoid clusters present in visceral adipose tissue omentum, play central roles in the regulation of abdominal immunity. Milky spots exhibit hybrid nature between secondary lymph organs and ectopic lymphoid tissues, yet the mechanism of their development and maturation is poorly understood. Here, we identified a subset of fibroblastic reticular cells (FRCs) that are uniquely present in omental milky spots. These FRCs were characterized by the expression of retinoic acid converting enzyme, Aldh1a2, and endothelial cell marker, Tie2, in addition to canonical FRC-associated genes. Diphtheria toxin-mediated ablation of Aldh1a2+ FRCs resulted in the alteration in milky spot structure with a significant reduction in size and cellularity. Mechanistically, Aldh1a2+ FRCs regulated the display of chemokine CXCL12 on high endothelial venules (HEVs), which recruit blood-borne lymphocytes from circulation. We further found that Aldh1a2+ FRCs are required for the maintenance of peritoneal lymphocyte composition. These results illustrate the homeostatic roles of FRCs in the formation of non-classical lymphoid tissues.

2023-02-14 | GSE224483 | GEO

Aldh1a2+ fibroblastic reticular cells regulate lymphocyte recruitment in omental milky spots (stromal fraction of wild-type)

2023-02-14 | GSE224315 | GEO

Activation of TLR9 signaling suppresses the immuno modulating functions of CD55lo fibroblastic reticular cells during bacterial peritonitis

Project description:Fibroblastic reticular cells (FRCs) are heterogeneous. We use single cell RNA sequencing to identify subsets of FRCs in fat-associated lymphoid clusters (FALC) in the mesenteric adipose tissue

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Fibroblastic reticular cells serve as primary immune checkpoint in visceral adipose tissues and secure peritoneal immunity

Project description:Immune protection of the body cavities depends on the swift activation of innate and adaptive immune responses in non-classical secondary lymphoid organs known as fat-associated lymphoid clusters (FALCs). While it is well-established that fibroblastic reticular cells (FRCs) are an integral component of the immune-stimulating infrastructure of lymph nodes and other classical secondary lymphoid organs, it has remained elusive whether and how FRCs in FALCs contribute to peritoneal immunity. Using FRC-specific gene targeting, we found that FALCs are underpinned by an elaborated FRC network and that initiation of peritoneal immunity was governed through FRC activation via MyD88-dependent innate immunological sensing. FRC-specific ablation of Myd88 expression blocked recruitment of inflammatory monocytes into FALCs and subsequent CD4+ T cell-dependent B-cell activation. Moreover, containment of Salmonella infection was compromised in conditionally Myd88-deficient mice indicating that FRCs in FALCs function as initial checkpoint in the orchestration of protective immune responses in the peritoneal cavity.

2018-06-12 | E-MTAB-6886 | biostudies-arrayexpress

Fibroblastic reticular cell lineage convergence in Peyer’s patches governs intestinal homeostasis

Project description:Peyer`s patches (PP) are underpinned by a dense network of FRCs. To elaborate the subset composition and topological organization of PP FRCs, we employed well-characterized Ccl19-Cre and Col6a1-Cre mouse models that permit FRC targeting in secondary lymphoid organs. To define PP FRC subsets and their relation to the observed FRC lineages, we isolated fibroblasts from Col6a1Eyfp and Ccl19Eyfp PPs and performed droplet-based single cell transcriptomics analysis. Taken together, the molecular definition of the PP FRC landscape reveals two FRC lineages furnishing distinct microenvironmental niches.

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Single-cell RNA sequencing reveals tissue-associated fibroblastic reticular cell heterogeneity in human secondary lymphoid organs

Project description:Fibroblastic reticular cells (FRCs) actively support secondary lymphoid organ (SLO) architecture. They regulate innate and adaptive immunity by compartmentalizing immune cells in specialized niches, and tightly interacting with them. The phenotypic and functional diversity of FRCs in human SLOs remains largely uncharacterized. We performed a comprehensive profiling of FRCs by single-cell RNA sequencing on human tonsils and lymph nodes. We provide the first complete description of the tonsillar CD45-negative compartment. We identified and validated in tonsil, a population of follicular dendritic cells restricted to the mantle zone and discovered two CCL21-negative FRC subsets intermingling with T-cell zone reticular cells in the extrafollicular space. We also identified podoplanin-positive epithelial cells as a potential plasma cell (PC) niche. We found two levels of FRC-associated diversity: i) tissue-specific subsets; ii) shared subsets with tissue-specific gene signatures. These findings shed new light on the role of FRCs in supporting SLO-specific immune responses.

2023-02-01 | GSE193449 | GEO

Human lymph node derived fibroblastic and double negative reticular cells alter their chemokines and cytokine expression profile following inflammatory stimuli

Project description:Lymph node is a secondary lymphoid organ that has structural organization related to their immune function, which is highly ordered and compartmentalized. Lymph nodes shelter immune cells and also fibroblastic-like cells such as fibroblastic reticular cells (FRCs). FRCs have mesodermal origin and are classically characterized by the expression of podoplanin (PDPN/gp38) and lack of CD31 expression. FRCs are implicated in several immune processes but the pathways subjacent their function are still a matter of research. Another cell population found in LNs, the double negative cells (DNCs), are even less known. They do not express PDPN or CD31 markers and a specific marker is absent, their localization within the LN is undefined and their phenotype or function, remain to be clarified. Although these cells have been studied in murine models, studies on human FRCs and DNCs are limited and therefore our study should contribute to the understanding of biology and function of these cells and should promote knowledge of efficiency and disorders in the lymph node immune response. This study evaluates gene expression and secretion of cytokines and chemokines in human-derived FRCs and DNCs during homeostasis and following inflammatory stimuli. Our results demonstrate that cytokines and chemokines secreted by human FRCs and DNCs partially differ from those identified in murine models. In addition, our study demonstrates that DNCs expressed a more varied of cytokines when compared with FRCs, while FRCs expressed a wider chemokines pattern. Such differences maybe related with specific functional differences between those cell populations within LNs.

2017-06-12 | GSE89612 | GEO

Cancer immunotherapies transition endothelial cells into HEVs that generate TCF1+ T lymphocyte niches through a feed-forward loop [SmartSeq2]

Project description:The lack of T cell infiltrates is a major obstacle to effective immunotherapy in cancer. Conversely, the formation of tumor-associated tertiary-lymphoid-like structures (TA-TLLSs), which are the local site of humoral and cellular immune responses against cancers, is associated with good prognosis, and they have recently been detected in immune checkpoint blockade (ICB)-responding patients. However, how these lymphoid aggregates develop remains poorly understood. By employing single-cell transcriptomics, endothelial fate mapping, and functional multiplex immune profiling, we demonstrate that antiangiogenic immune-modulating therapies evoke transdifferentiation of postcapillary venules into inflamed high-endothelial venules (HEVs) via lymphotoxin/lymphotoxin beta receptor (LT/LTβR) signaling. In turn, tumor HEVs boost intratumoral lymphocyte influx and foster permissive lymphocyte niches for PD1- and PD1+TCF1+ CD8 T cell progenitors that differentiate into GrzB+PD1+ CD8 T effector cells. Tumor-HEVs require continuous CD8 and NK cell-derived signals revealing that tumor HEV maintenance is actively sculpted by the adaptive immune system through a feed-forward loop.

2022-11-02 | GSE198069 | GEO

Cancer immunotherapies transition endothelial cells into HEVs that generate TCF1+ T lymphocyte niches through a feed-forward loop [10X Genomics]

2022-11-02 | GSE198079 | GEO

Transcriptome Analysis of Tumor Associated High Endothelial Venules in Breast Cancer

Project description:High endothelial venules (HEVs) are specialized post-capillary venules that recruit naïve lymphocytes to the lymph nodes and are essential for the development of adaptive immunity. HEVs can also develop in tumors. These specialized tumor vessels are thought to be important for recruiting naïve T cells and B cells into tumors and locally enhancing anti-tumor immunity by supporting the formation of tertiary lymphoid structures. By a comparative transcriptome analysis in human breast cancer, we investigated differentially expressed genes between tumor-associated HEVs and the rest of the tumor vasculature. Tumor vessels highly expressing HEV-upregulated genes, such as the homeobox gene MEOX2 and the tetraspanin gene TSPAN7, were associated with extensive infiltration of T and B lymphocytes and the occurrence of tertiary lymphoid structures, which is known to predict therapeutic responses to immune checkpoint inhibitors. Moreover, high transcript counts of these genes in clinical tumor specimens were associated with a significant survival benefit in advanced breast cancer. The molecular signature of HEVs identified here may be useful for guiding immunotherapies and provide a new direction for investigating tumor-associated HEVs and their clinical significance.

2022-03-31 | GSE196703 | GEO

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