scholarly journals Characterization of Leptin Receptor+ Stromal Cells in Lymph Node

2022 ◽  
Vol 12 ◽  
Author(s):  
Liwei Jiang ◽  
Mine Yilmaz ◽  
Mayuko Uehara ◽  
Cecilia B. Cavazzoni ◽  
Vivek Kasinath ◽  
...  
Keyword(s):  
Lymph Node ◽  
Stromal Cells ◽  
Leptin Receptor ◽  
Inflammatory Responses ◽  
Conditional Knockout ◽  
High Endothelial Venules ◽  
Stromal Compartment ◽  
Leptin Signaling ◽  
Cell Dysfunction ◽  
Reticular Cells

Lymph node (LN)-resident stromal cells play an essential role in the proper functioning of LNs. The stromal compartment of the LN undergoes significant compensatory changes to produce a milieu amenable for regulation of the immune response. We have identified a distinct population of leptin receptor-expressing (LepR+) stromal cells, located in the vicinity of the high endothelial venules (HEVs) and lymphatics. These LepR+ stromal cells expressed markers for fibroblastic reticular cells (FRCs), but they lacked markers for follicular dendritic cells (FDCs) and marginal reticular cells (MRCs). Leptin signaling deficiency led to heightened inflammatory responses within the LNs of db/db mice, leakiness of HEVs, and lymphatic fragmentation. Leptin signaling through the JAK/STAT pathway supported LN stromal cell survival and promoted the anti-inflammatory properties of these cells. Conditional knockout of the LepR+ stromal cells in LNs resulted in HEV and extracellular matrix (ECM) abnormalities. Treatment of ob/ob mice with an agonist leptin fusion protein restored the microarchitecture of LNs, reduced intra-LN inflammatory responses, and corrected metabolic abnormalities. Future studies are needed to study the importance of LN stomal cell dysfunction to the pathogenesis of inflammatory responses in type 2 diabetes (T2D) in humans.

scholarly journals Lymph node stromal CCL2 limits antibody responses

2020 ◽  
Vol 5 (45) ◽  
pp. eaaw0693 ◽  
Author(s):  
Dragos C. Dasoveanu ◽  
Hyeung Ju Park ◽  
Catherine L. Ly ◽  
William D. Shipman ◽  
Susan Chyou ◽  
...  
Keyword(s):  
Lymph Node ◽  
Stromal Cells ◽  
Plasma Cells ◽  
Regulatory Function ◽  
Dependent Manner ◽  
Stromal Compartment ◽  
Vascular Activity ◽  
Chemokine Ligand ◽  
Reticular Cells ◽  
Chemokine Ligand 2

Nonhematopoietic stromal cells in lymph nodes such as fibroblastic reticular cells (FRCs) can support the survival of plasmablasts and plasma cells [together, antibody-forming cells (AFCs)]. However, a regulatory function for the stromal compartment in AFC accumulation has not been appreciated. Here, we show that chemokine ligand 2 (CCL2)–expressing stromal cells limit AFC survival. FRCs express high levels of CCL2 in vessel-rich areas of the T cell zone and the medulla, where AFCs are located. FRC CCL2 is up-regulated during AFC accumulation, and we use lymph node transplantation to show that CCL2 deficiency in BP3+ FRCs and lymphatic endothelial cells increases AFC survival without affecting B or germinal center cell numbers. Monocytes are key expressers of the CCL2 receptor CCR2, as monocyte depletion and transfer late in AFC responses increases and decreases AFC accumulation, respectively. Monocytes express reactive oxygen species (ROS) in an NADPH oxidase 2 (NOX2)–dependent manner, and NOX2-deficient monocytes fail to reduce AFC numbers. Stromal CCL2 modulates both monocyte accumulation and ROS production, and is regulated, in part, by manipulations that modulate vascular permeability. Together, our results reveal that the lymph node stromal compartment, by influencing monocyte accumulation and functional phenotype, has a regulatory role in AFC survival. Our results further suggest a role for inflammation-induced vascular activity in tuning the lymph node microenvironment. The understanding of stromal-mediated AFC regulation in vessel-rich environments could potentially be harnessed to control antibody-mediated autoimmunity.

scholarly journals Lymph-Borne Chemokines and Other Low Molecular Weight Molecules Reach High Endothelial Venules via Specialized Conduits While a Functional Barrier Limits Access to the Lymphocyte Microenvironments in Lymph Node Cortex

2000 ◽  
Vol 192 (10) ◽  
pp. 1425-1440 ◽  
Author(s):  
J. Elizabeth Gretz ◽  
Christopher C. Norbury ◽  
Arthur O. Anderson ◽  
Amanda E.I. Proudfoot ◽  
Stephen Shaw
Keyword(s):  
Lymph Node ◽  
Basement Membranes ◽  
High Endothelial Venules ◽  
Reticular Fibers ◽  
Lymph Node Enlargement ◽  
Subcapsular Sinus ◽  
Sinus Floor ◽  
Draining Lymph Node ◽  
Reticular Cells ◽  
Draining Lymph Nodes

Lymph-borne, soluble factors (e.g., chemokines and others) influence lymphocyte recirculation and endothelial phenotype at high endothelial venules (HEVs) in lymph node cortex. Yet the route lymph-borne soluble molecules travel from the subcapsular sinus to the HEVs is unclear. Therefore, we injected subcutaneously into mice and rats a wide variety of fluorophore-labeled, soluble molecules and examined their distribution in the draining lymph nodes. Rather than percolating throughout the draining lymph node, all molecules, including microbial lipopolysaccharide, were very visible in the subcapsular and medullary sinuses but were largely excluded from the cortical lymphocyte microenvironments. Exclusion prevailed even during the acute lymph node enlargement accompanying viral infection. However, low molecular mass (MW) molecules, including chemokines, did gain entry into the cortex, but in a very defined manner. Low MW, fluorophore-labeled molecules highlighted the subcapsular sinus, the reticular fibers, and the abluminal and luminal surfaces of the associated HEVs. These low MW molecules were in the fibers of the reticular network, a meshwork of collagen fibers ensheathed by fibroblastic reticular cells that connects the subcapsular sinus floor and the HEVs by intertwining with their basement membranes. Thus, low MW, lymph-borne molecules, including chemokines, traveled rapidly from the subcapsular sinus to the HEVs using the reticular network as a conduit.

scholarly journals IL-7–producing stromal cells are critical for lymph node remodeling

Blood ◽  
2012 ◽  
Vol 120 (24) ◽  
pp. 4675-4683 ◽  
Author(s):  
Lucas Onder ◽  
Priyanka Narang ◽  
Elke Scandella ◽  
Qian Chai ◽  
Maria Iolyeva ◽  
...  
Keyword(s):  
Lymph Node ◽  
Stromal Cells ◽  
Fluid Transport ◽  
De Novo ◽  
Artificial Chromosome ◽  
Surrounding Tissue ◽  
Lymphocyte Homeostasis ◽  
Reticular Cells ◽  
Secondary Lymphoid Organs ◽  
Fibroblastic Reticular Cells

AbstractNonhematopoietic stromal cells of secondary lymphoid organs form important scaffold and fluid transport structures, such as lymph node (LN) trabeculae, lymph vessels, and conduits. Furthermore, through the production of chemokines and cytokines, these cells generate a particular microenvironment that determines lymphocyte positioning and supports lymphocyte homeostasis. IL-7 is an important stromal cell-derived cytokine that has been considered to be derived mainly from T-cell zone fibroblastic reticular cells. We show here that lymphatic endothelial cells (LECs) are a prominent source of IL-7 both in human and murine LNs. Using bacterial artificial chromosome transgenic IL-7–Cre mice, we found that fibroblastic reticular cells and LECs strongly up-regulated IL-7 expression during LN remodeling after viral infection and LN reconstruction after avascular transplantation. Furthermore, IL-7–producing stromal cells contributed to de novo formation of LyveI-positive lymphatic structures connecting reconstructed LNs with the surrounding tissue. Importantly, diphtheria toxin–mediated depletion of IL-7–producing stromal cells completely abolished LN reconstruction. Taken together, this study identifies LN LECs as a major source of IL-7 and shows that IL-7–producing stromal cells are critical for reconstruction and remodeling of the distinct LN microenvironment.

scholarly journals Lymph Node Stromal Cells From Different Draining Areas Distinctly Regulate the Development of Chronic Intestinal Inflammation

2021 ◽  
Vol 11 ◽  
Author(s):  
Marijana Basic ◽  
Pia Pascale Peppermüller ◽  
Silvia Bolsega ◽  
André Bleich ◽  
Melanie Bornemann ◽  
...  
Keyword(s):  
Immune Response ◽  
Lymph Node ◽  
Lymph Nodes ◽  
Stromal Cells ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Peripheral Lymph ◽  
Intestinal Immune System ◽  
Chronic Intestinal Inflammation ◽  
Lymph Node Stromal Cells

The balance between the responsiveness of the intestinal immune system and the gut environment is fundamental for the maintenance of intestinal homeostasis, which is required for an adequate recognition of entering antigens. The disruption of this homeostasis by exaggerated immune response to harmless antigens can lead to the development of intestinal disorders such as inflammatory bowel disease. Stromal cells are sessile non-hematopoietic cells that build the backbone of the lymph node, an important site for the immune response induction, but also contribute to immune response and tolerance induction. However, the knowledge about the role of stromal cells in the regulation of inflammatory responses is still limited. Therefore, in this study we analyzed the influence of stromal cells on the development of chronic intestinal inflammation. Here, we show that intestinal inflammation alters the immune activation of the mesenteric lymph node-derived stromal cells. Podoplanin+ and CD21/35+ stromal cells showed increased expression of MHC class II molecules, but CD106 expression on CD21/35+ cells was reduced. Stromal cells secreted cytokines and chemokines such as CCL7 and CXCL16 influenced the gut-homing phenotype and proliferation of CD4+ and CD8+ T cells. Furthermore, stromal cells of peripheral lymph nodes transplanted into the mesentery attenuated colitis severity in B6-Il10-/- mice. The reduced colitis severity in these mice was associated with increased expression of IL4 and distinct activation pattern of stromal cells derived from transplanted peripheral lymph nodes. Altogether, our results demonstrate that lymph node stromal cells impact development of chronic colitis via T cell induction. Moreover, lymph node stromal cells from different draining area due to neonatally imprinted processes distinctly regulate the induction of immune responses.

scholarly journals A Single-Cell Atlas of Nonhematopoietic Cells in Human Lymph Node and Lymphoma Reveals Landscape of Stromal Remodeling

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 447-447
Author(s):  
Yoshiaki Abe ◽  
Mamiko Sakata-Yanagimoto ◽  
Manabu Fujisawa ◽  
Hiroaki Miyoshi ◽  
Yasuhito Suehara ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Lymph Node ◽  
B Cell ◽  
Single Cell ◽  
Stromal Cells ◽  
Clustering Analysis ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Human Lymph Node ◽  
Reticular Cells

Abstract Background: Activities of nonhematopoietic cells (NHCs) reportedly underlie lymphomagenesis. In follicular lymphoma (FL), mesenchymal stromal cells (SCs) including follicular dendritic cells (FDCs) have been shown to facilitate FL expansion. However, comprehensive understanding of lymphoma NHC activities have been hampered by indefinite NHC heterogeneity even in normal human lymph node (LN). Indeed, human LN blood endothelial cells (BECs) and non-endothelial stromal cells (NESCs) have not been analyzed at single-cell resolution. Here, we aimed to construct a single-cell atlas of NHCs in human LN applicable to lymphoma researches. We also sought to reveal the landscape of stromal remodeling in lymphomas, particularly in FL, to advance understanding of stromal contributions in lymphomagenesis. Methods: We prospectively performed single-cell RNA sequencing of NHCs (>100,000 cells) extracted from 27 human samples including metastasis-free LN (MFLN; n=9), nodal FL (n=10), peripheral T-cell lymphoma (PTCL; n=5), and diffuse large B-cell lymphoma transformed from FL (tDLBCL; n=3). Data from MFLN samples were used for the construction of NHC atlas. Immunofluorescence (IF) staining was performed to investigate the existence and topological localizations of each NHC subcluster in the LN. Using the NHC atlas, we performed comprehensive comparative analysis with FL NHCs by differentially-expressed gene (DEG) and intercellular ligand-receptor analyses. We also investigated the prognostic impact of putative stroma-derived biomarkers using deposited microarray data of FL patients. Finally, we examined the applicability of the atlas to NHCs from other lymphoma subtypes by analyzing PTCL and tDLBCL NHCs. Data analysis was performed through multiple pipelines including Seurat, Monocle3, and CellphoneDB. Results: Graph-based clustering analysis revealed that the transcriptional features of NHC subpopulations in MFLN are detectable in FL NHCs. Unsupervised sub-clustering analysis of BECs, lymphatic endothelial cells (LECs), and NESCs revealed 10, 8, and 12 subclusters, respectively, including some lacking mouse counterpart. IF staining successfully identified each NHC subcluster and its localization in the LN. In FL NHCs, the proportion of arterial BEC subclusters markedly increased relative to MFLN, while the proportion of LECs decreased. In FL NESCs, the proportion of marginal reticular cells (MRCs) as well as FDCs greatly increased. DEG analysis revealed that the greatest changes in gene expression occurs in NESC subclusters, particularly in MRCs, T-zone reticular cells (TRCs), pericytes, and FDCs. Notably, in some NESC subclusters, we observed marked upregulation of genes relevant to solid cancers but previously not described in lymphomas (e.g. POSTN, EGFL6, and FAP). Combined interactome and DEG analysis revealed 60 FL-specific interactions between NHC subclusters and malignant B cells. For example, interactions mediated through stroma-derived CD70 were enhanced at medullary SC subclusters and SCs at LN capsule adventitia. Additionally, the CCR7-CCL19 interaction and interactions via B-cell activating factor (BAFF) were unexpectedly upregulated at non-TRC SC and medullary SC subclusters, respectively. Also, the CXCL13-CXCR5 axis was highly activated in MRCs, collectively indicating that non-FDC SCs vigorously participate in FL cell expansion and/or infiltration into extra-follicular lesions. Some intercellular interactions were functionally validated by in vitro binding assays. Based on this dataset, we identified putative stroma-derived biomarkers linked to unfavorable prognosis in FL patients including TDO2, encoding immune-modulators, and LY6H and LOX, tip cell markers. We finally confirmed that NHC subclusters identified in our atlas were also detectable in NHCs of more aggressive lymphoma subtypes including PTCL and tDLBCL. Notably, we found that extra-follicular SCs had further differentiated into follicular SCs in tDLBCL, likely representing a terminal form of stromal remodeling in FL. Conclusion: We constructed a comprehensive single-cell atlas of NHCs in human LN highly applicable to lymphoma NHC researches and revealed a total of 30 NHC subclusters. Our study largely updates NHC taxonomy in LNs and provides a rich resource and deeper insights into lymphoma biology, a contribution that should advance lymphoma management and therapy. Figure 1 Figure 1. Disclosures Usuki: Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Research Funding, Speakers Bureau; Ono Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K.: Research Funding; Celgene K.K.: Research Funding, Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Nippon-Boehringer-Ingelheim Co., Ltd.: Research Funding; Mundipharma K.K.: Research Funding; Amgen-Astellas Biopharma K.K.: Research Funding; Nippon-Shinyaku Co., Ltd.: Research Funding, Speakers Bureau; Kyowa-Kirin Co., Ltd.: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Research Funding, Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; MSD K.K.: Research Funding, Speakers Bureau; PharmaEssentia Japan KK: Research Funding, Speakers Bureau; Yakult Honsha Co., Ltd.: Research Funding, Speakers Bureau; Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; Sumitomo-Dainippon Pharma Co., Ltd.: Research Funding; SymBio Pharmaceuticals Ltd.: Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Research Funding; Bristol-Myers-Squibb K.K.: Research Funding, Speakers Bureau; Apellis Pharmaceuticals, Inc.: Research Funding; AbbVie GK: Research Funding, Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Incyte Biosciences Japan G.K.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sanofi K.K.: Speakers Bureau; Amgen K.K.: Research Funding.

scholarly journals Remodeling of the Lymph Node High Endothelial Venules Reflects Tumor Invasiveness in Breast Cancer and is Associated with Dysregulation of Perivascular Stromal Cells

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 211
Author(s):  
Tove Bekkhus ◽  
Teemu Martikainen ◽  
Anna Olofsson ◽  
Mathias Franzén Boger ◽  
Daniel Vasiliu Bacovia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Responses ◽  
Stromal Cells ◽  
Nodal Metastasis ◽  
Organ Donors ◽  
High Endothelial Venules ◽  
Tumor Invasiveness ◽  
Non Invasive ◽  
Reticular Cells ◽  
Draining Lymph Nodes

The tumor-draining lymph nodes (TDLNs) are primary sites for induction of tumor immunity. They are also common sites of metastasis, suggesting that tumor-induced mechanisms can subvert anti-tumor immune responses and promote metastatic seeding. The high endothelial venules (HEVs) together with CCL21-expressing fibroblastic reticular cells (FRCs) are essential for lymphocyte recruitment into the LNs. We established multicolor antibody panels for evaluation of HEVs and FRCs in TDLNs from breast cancer (BC) patients. Our data show that patients with invasive BC display extensive structural and molecular remodeling of the HEVs, including vessel dilation, thinning of the endothelium and discontinuous expression of the HEV-marker PNAd. Remodeling of the HEVs was associated with dysregulation of CCL21 in perivascular FRCs and with accumulation of CCL21-saturated lymphocytes, which we link to loss of CCL21-binding heparan sulfate in FRCs. These changes were rare or absent in LNs from patients with non-invasive BC and cancer-free organ donors and were observed independent of nodal metastasis. Thus, pre-metastatic dysregulation of core stromal and vascular functions within TDLNs reflect the primary tumor invasiveness in BC. This adds to the understanding of cancer-induced perturbation of the immune response and opens for prospects of vascular and stromal changes in TDLNs as potential biomarkers.

scholarly journals Reproducible Isolation of Lymph Node Stromal Cells Reveals Site-Dependent Differences in Fibroblastic Reticular Cells

2011 ◽  
Vol 2 ◽  
Author(s):  
Anne L. Fletcher ◽  
Deepali Malhotra ◽  
Sophie E. Acton ◽  
Veronika Lukacs-Kornek ◽  
Angelique Bellemare-Pelletier ◽  
...  
Keyword(s):  
Lymph Node ◽  
Stromal Cells ◽  
Reticular Cells ◽  
Lymph Node Stromal Cells ◽  
Fibroblastic Reticular Cells

Human Mesenchymal Stem Cells as Precursors of Functional Fibroblastic Reticular Cells: Implications for the Physiopathology of Secondary Lymphoid Organs.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2310-2310
Author(s):  
Karin Tarte ◽  
Patricia Ame-Thomas ◽  
Hélène Maby ◽  
Sylvie Caulet-Maugendre ◽  
Rachel Jean ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Lymph Node ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Lymphoid Organs ◽  
Tnf Α ◽  
Reticular Cells ◽  
Secondary Lymphoid Organs

Abstract Several subsets of stromal cells are found among secondary lymphoid organs where they play a key role in the initiation and maintenance of immune response. In particular, fibroblastic reticular cells (FRC) of the paracortex secrete extracellular matrix (ECM) components that constitute a dense network of conduits allowing antigens carried within the subcapsular afferent lymph to reach the lumen of the medullary high endothelial venules. FRC produce also several chemokines that recruit T, B, and dendritic cells from blood and favour their reciprocal interactions. In addition, follicular dendritic cells (FDC) are located exclusively into germinal centers and allow normal B-cell selection through a complex set of survival signals, including BCR-mediated signal, chemokines and adhesion molecules. FRC and FDC networks are phenotypically and probably functionally altered during development of follicular lymphomas and diffuse large B cell lymphomas, the two most frequent Non-Hodgkin Lymphomas. FRC and FDC are supposed to be of mesenchymal origin even if no conclusive work has been conducted to date in human. We have obtained 15 tonsil-derived stromal cell lines, that displayed all the morphologic, phenotypic, and functional characteristics of FRC, including synthesis of inflammatory (CXCL10, CXCL9, CCL5) and lymph-node specific (CCL19, CCL21) chemokines, and secretion of ECM organized in a reticular meshwork after long-term culture in the presence of TNF-α and lymphotoxin-α1β2 (LT). These cells induced tonsil leukocyte migration and adhesion in vitro. Tonsil-derived stromal cells expressed LTβR, TNFR, and CD40 but were negative for FDC specific markers, such as CD21 or CXCL13, even following in vitro stimulation by TNF-α, LT, and trimeric CD40L. Interestingly, such TNF and LT-dependent FRC differentiation could also be induced in adult bone marrow-derived mesenchymal stem cells (MSC). In addition, MSC-like cells able to differentiate along osteogenic, adipogenic, and chondrogenic lineages at the clonal level were found in normal tonsils. These data shed new lights on our current understanding of lymph node stromal cell origin and strongly suggest that MSC are the precursors of FRC in secondary lymphoid organs, and perhaps in bone marrow in case of FL involvement where ectopic lymph node-like stromal cells are detected in close association with tumor cells. In conclusion, MSC and their progeny trigger differential immune effects, depending on cytokine context, localization and cell contact with immune cells. These properties are probably modified during lymphomas where the contact between malignant B cells and stromal cells is crucial for tumor development.

scholarly journals Anti-CD43 Inhibition of  T Cell Homing

1997 ◽  
Vol 185 (8) ◽  
pp. 1493-1498 ◽  
Author(s):  
Leslie M. McEvoy ◽  
Hailing Sun ◽  
John G. Frelinger ◽  
Eugene C. Butcher
Keyword(s):  
Lymph Node ◽  
T Cell ◽  
Inflammatory Responses ◽  
Lymphocyte Activation ◽  
Cell Interaction ◽  
Lymphoid Tissues ◽  
High Endothelial Venules ◽  
Novel Target

The homing of lymphocytes from the blood is controlled by specialized processes of lymphocyte–endothelial cell interaction. Interference with these processes offers the potential to manipulate lymphocyte traffic, and thus to modulate normal and pathologic immune and inflammatory responses. We selected antilymphocyte monoclonal antibodies (mAbs) for inhibition of lymphocyte binding in vitro to lymph node high endothelial venules (HEV), specialized vessels that support lymphocyte recruitment into lymph nodes. mAb L11 blocks T cell binding to lymph node and Peyer's patch HEV and inhibits T cell extravasation from the blood into organized secondary lymphoid tissues. In contrast, L11 has no effect on lymphocyte binding to purified vascular ligands for L-selectin, α4β7, or LFA-1, suggesting that it inhibits by a novel mechanism. The L11 antigen is CD43, a sialomucin implicated in vitro in regulation of lymphocyte activation, whose expression is often dysregulated in the Wiskott-Aldrich syndrome. CD43 represents a novel target for experimental and therapeutic manipulation of lymphocyte traffic and may help regulate T cell distribution in vivo.

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