The Experts below are selected from a list of 5631 Experts worldwide ranked by ideXlab platform
Jeffrey L Browning - One of the best experts on this subject based on the ideXlab platform.
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follicular dendritic cells emerge from ubiquitous perivascular precursors
Cell, 2012Co-Authors: Nike J. Krautler, Jan Kranich, Jeffrey L Browning, Petra Schwarz, Veronika Kana, Yinghua Tian, Dushan Perera, Doreen Lemm, Annika Armulik, Michelle D TallquistAbstract:The differentiation of follicular dendritic cells (FDC) is essential to the remarkable microanatomic plasticity of lymphoid follicles. Here we show that FDC arise from ubiquitous perivascular precursors (preFDC) expressing platelet-derived growth factor receptor β (PDGFRβ). PDGFRβ-Cre-driven reporter gene recombination resulted in FDC labeling, whereas conditional ablation of PDGFRβ(+)-derived cells abolished FDC, indicating that FDC originate from PDGFRβ(+) cells. Lymphotoxin-α-overexpressing prion protein (PrP)(+) kidneys developed PrP(+) FDC after transplantation into PrP(-) mice, confirming that preFDC exist outside lymphoid organs. Adipose tissue-derived PDGFRβ(+) stromal-vascular cells responded to FDC maturation factors and, when transplanted into Lymphotoxin β receptor (LTβR)(-) kidney capsules, differentiated into Mfge8(+)CD21/35(+)FcγRIIβ(+)PrP(+) FDC capable of trapping immune complexes and recruiting B cells. Spleens of lymphocyte-deficient mice contained perivascular PDGFRβ(+) FDC precursors whose expansion required both lymphoid tissue inducer (LTi) cells and Lymphotoxin. The ubiquity of preFDC and their strategic location at blood vessels may explain the de novo generation of organized lymphoid tissue at sites of lymphocytic inflammation.
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regulation of t h 2 development by cxcr5 dendritic cells and Lymphotoxin expressing b cells
Nature Immunology, 2012Co-Authors: Beatriz Leon, Jeffrey L Browning, Andre Ballesterostato, Robert Dunn, Troy D Randall, Frances E LundAbstract:In lymph nodes, cellular positioning can dictate the immune response. Lund and colleagues show that nematode infection triggers interactions between Lymphotoxin-producing B cells and CXCR5+ dendritic cells and CD4+ T cells to initiate T helper type 2 responses.
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regulation of t h 2 development by cxcr5 dendritic cells and Lymphotoxin expressing b cells
Nature Immunology, 2012Co-Authors: Beatriz Leon, Jeffrey L Browning, Andre Ballesterostato, Robert Dunn, Troy D Randall, Frances E LundAbstract:Although cognate encounters between antigen-bearing dendritic cells (DCs) that express the chemokine receptor CCR7 and CCR7(+) naive T cells take place in the T cell zone of lymph nodes, it is unknown whether the colocalization of DCs and T cells in the T cell area is required for the generation of effector cells. Here we found that after infection with an intestinal nematode, antigen-bearing DCs and CD4(+) T cells upregulated the chemokine receptor CXCR5 and localized together outside the T cell zone by a mechanism dependent on the chemokine CXCL13, B cells and Lymphotoxin. Notably, Lymphotoxin-expressing B cells, CXCR5-expressing DCs and T cells, and CXCL13 were also necessary for development of interleukin 4 (IL-4)-producing type 2 helper T cells (T(H)2 cells), which suggests that T(H)2 differentiation can initiate outside the T cell zone.
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inhibition of the Lymphotoxin pathway as a therapy for autoimmune disease
Immunological Reviews, 2008Co-Authors: Jeffrey L BrowningAbstract:SUMMARY The Lymphotoxin (LT) system is part of the tumor necrosis factor family and is required for lymph node development. It has provided a wonderful tool for the dissection of processes critical not only for lymphoid organ development but also the maintenance of the adult immune architecture and the formation of ectopic organized lymphoid tissues in chronically inflamed sites. A soluble Lymphotoxin-beta receptor-immunoglobulin (LTbetaR-Ig) fusion protein can block this pathway and is currently being tested in the treatment of autoimmune disease. This review focuses on the immunological consequences of combined LT and LIGHT inhibition with LTbetaR-Ig administration as distinct from the developmental biology.
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Lymphotoxin β receptor signaling is required for the homeostatic control of hev differentiation and function
Immunity, 2005Co-Authors: Jeffrey L Browning, Apinya Ngamek, Norm Allaire, Evangelia Notidis, Jane A Hunt, Steven Perrin, Roy A FavaAbstract:The Lymphotoxin axis is important for the maintenance of several specialized lymphoid microenvironments in secondary lymphoid tissue. Lymphoid-tissue architecture is highly plastic and requires continual homeostatic signaling to maintain its basal functional state. The cellularity of lymph nodes in adult mice was reduced by systemic blockade of Lymphotoxin-beta receptor (LTbeta R) signaling with a soluble decoy receptor both in resting and reactive settings. This reduction in cellularity resulted from greatly impaired lymphocyte entry into lymph nodes due to decreased levels of peripheral lymph node addressing (PNAd) and MAdCAM on high endothelial venules (HEV). LTbeta R signaling was required to maintain normal levels of RNA expression of MAdCAM, and also of PNAd by regulating the expression of key enzymes and scaffold proteins required for its assembly. Thus, the homeostatic maintenance of functional HEV status in adult mice relies largely on LTbeta R signaling.
Jeanphilippe Girard - One of the best experts on this subject based on the ideXlab platform.
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regulation of tumor associated high endothelial venules by dendritic cells a new opportunity to promote lymphocyte infiltration into breast cancer
OncoImmunology, 2013Co-Authors: Ludovic Martinet, Jeanphilippe GirardAbstract:Accumulating evidence suggests that high-endothelial venules (HEVs) represent major gateways for the infiltration of lymphocytes within neoplastic lesions. However, the origin of these vessels in human neoplasms remains elusive. We have recently discovered a link between Lymphotoxin β-producing dendritic cells and tumor-associated HEVs.
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high endothelial venule blood vessels for tumor infiltrating lymphocytes are associated with Lymphotoxin β producing dendritic cells in human breast cancer
Journal of Immunology, 2013Co-Authors: Jeanphilippe Girard, Ludovic Martinet, Thomas Filleron, Sophie Le Guellec, Philippe Rochaix, I GarridoAbstract:Blood vessels and tumor angiogenesis are generally associated with tumor growth and poor clinical outcome of cancer patients. However, we recently discovered that some blood vessels present within the tumor microenvironment can be associated with favorable prognosis. These vessels, designated tumor high endothelial venules (HEVs), appear to facilitate tumor destruction by allowing high levels of lymphocyte infiltration into tumors. In this study, we investigated the mechanisms regulating HEV blood vessels in human breast cancer. We found that Lymphotoxin β was overexpressed in tumors containing high densities of HEVs (HEVhigh) and correlated to DC-LAMP, a marker of mature DCs. DCs were the main producers of Lymphotoxin β in freshly resected HEVhigh breast tumor samples, and the density of DC-LAMP+ DCs clusters was strongly correlated with the density of tumor HEVs, T and B cell infiltration, and favorable clinical outcome in a retrospective cohort of 146 primary invasive breast cancer patients. Densities of tumor HEVs and DC-LAMP+ DCs were strongly reduced during breast cancer progression from in situ carcinoma to invasive carcinoma, suggesting that loss of tumor HEVs is a critical step during breast cancer progression. Finally, an increase in the infiltration of regulatory T cells was observed in HEVhigh breast tumors, indicating that tumor HEVs can develop in the presence of regulatory T cells. Together, our results support a key role for DCs and DC-derived Lymphotoxin in the formation of tumor HEVs. These findings are important because novel therapeutic strategies based on the modulation of tumor HEVs could have a major impact on clinical outcome of cancer patients.
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dendritic cells control lymphocyte entry to lymph nodes through high endothelial venules
Nature, 2011Co-Authors: Christine Moussion, Jeanphilippe GirardAbstract:Christine Moussion and Jean-Philippe Girard report that dendritic cells in the immune system have an unexpected immune surveillance role in lymphocyte recirculation during homeostasis. Lymphotoxin ligands derived from dendritic cells promote the growth of high endothelial venules — blood vessels specialized in lymphocyte recruitment — which control the entry of naive lymphocytes from the blood into lymph nodes. While patrolling the body in search of foreign antigens, naive lymphocytes continuously circulate from the blood, through the lymph nodes, into the lymphatic vessels and back to the blood1,2. This process, called lymphocyte recirculation, provides the body with effective immune surveillance for foreign invaders and for alterations to the body’s own cells. However, the mechanisms that regulate lymphocyte recirculation during homeostasis remain incompletely characterized. Here we show that dendritic cells (DCs), which are well known for their role in antigen presentation to T lymphocytes3, control the entry of naive lymphocytes to lymph nodes by modulating the phenotype of high endothelial venules (HEVs), which are blood vessels specialized in lymphocyte recruitment2,4,5. We found that in vivo depletion of CD11c+ DCs in adult mice over a 1-week period induces a reduction in the size and cellularity of the peripheral and mucosal lymph nodes. In the absence of DCs, the mature adult HEV phenotype reverts to an immature neonatal phenotype, and HEV-mediated lymphocyte recruitment to lymph nodes is inhibited. Co-culture experiments showed that the effect of DCs on HEV endothelial cells is direct and requires Lymphotoxin-β-receptor-dependent signalling. DCs express Lymphotoxin, and DC-derived Lymphotoxin is important for lymphocyte homing to lymph nodes in vivo. Together, our results reveal a previously unsuspected role for DCs in the regulation of lymphocyte recirculation during immune surveillance.
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Dendritic cells control lymphocyte entry to lymph nodes through high endothelial venules
Nature, 2011Co-Authors: Christine Moussion, Jeanphilippe GirardAbstract:While patrolling the body in search of foreign antigens, naive lymphocytes continuously circulate from the blood, through the lymph nodes, into the lymphatic vessels and back to the blood. This process, called lymphocyte recirculation, provides the body with effective immune surveillance for foreign invaders and for alterations to the body's own cells. However, the mechanisms that regulate lymphocyte recirculation during homeostasis remain incompletely characterized. Here we show that dendritic cells (DCs), which are well known for their role in antigen presentation to T lymphocytes, control the entry of naive lymphocytes to lymph nodes by modulating the phenotype of high endothelial venules (HEVs), which are blood vessels specialized in lymphocyte recruitment. We found that in vivo depletion of CD11c(+) DCs in adult mice over a 1-week period induces a reduction in the size and cellularity of the peripheral and mucosal lymph nodes. In the absence of DCs, the mature adult HEV phenotype reverts to an immature neonatal phenotype, and HEV-mediated lymphocyte recruitment to lymph nodes is inhibited. Co-culture experiments showed that the effect of DCs on HEV endothelial cells is direct and requires Lymphotoxin-β-receptor-dependent signalling. DCs express Lymphotoxin, and DC-derived Lymphotoxin is important for lymphocyte homing to lymph nodes in vivo. Together, our results reveal a previously unsuspected role for DCs in the regulation of lymphocyte recirculation during immune surveillance.
Hugh O Mcdevitt - One of the best experts on this subject based on the ideXlab platform.
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disrupted splenic architecture but normal lymph node development in mice expressing a soluble Lymphotoxin beta receptor igg1 fusion protein
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: R Ettinger, J L Browning, Sara A Michie, Van Ewijk W, Hugh O McdevittAbstract:Early in ontogeny, the secondary lymphoid organs become populated with numerous cells of mesodermal origin which forms both the lymphoid and stromal elements. The critical receptor/ligand interactions necessary for lymphoid organogenesis to occur are for the most part unknown. Although Lymphotoxin-α (LTα) has been shown to be required for normal lymph node, Peyer’s patch, and splenic development, it is unclear if soluble LTα3, and/or cell-bound Lymphotoxin-αβ (LTαβ) mediate these developmental events. Here we report that blocking LTαβ/Lymphotoxin-β receptor (LTβR) interaction in vivo by generating mice which express a soluble LTβR–Fc fusion protein driven by the human cytomegalovirus promoter results in an array of anatomic abnormalities affecting both the spleen and Peyer’s patches, but not the lymph nodes. These results demonstrate that surface LTαβ ligand plays a critical role in normal lymphoid organ development.
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disrupted splenic architecture but normal lymph node development in mice expressing a soluble Lymphotoxin β receptor igg1 fusion protein
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: R Ettinger, Jeffrey L Browning, Sara A Michie, Willem Van Ewijk, Hugh O McdevittAbstract:Early in ontogeny, the secondary lymphoid organs become populated with numerous cells of mesodermal origin which forms both the lymphoid and stromal elements. The critical receptor/ligand interactions necessary for lymphoid organogenesis to occur are for the most part unknown. Although Lymphotoxin-α (LTα) has been shown to be required for normal lymph node, Peyer’s patch, and splenic development, it is unclear if soluble LTα3, and/or cell-bound Lymphotoxin-αβ (LTαβ) mediate these developmental events. Here we report that blocking LTαβ/Lymphotoxin-β receptor (LTβR) interaction in vivo by generating mice which express a soluble LTβR–Fc fusion protein driven by the human cytomegalovirus promoter results in an array of anatomic abnormalities affecting both the spleen and Peyer’s patches, but not the lymph nodes. These results demonstrate that surface LTαβ ligand plays a critical role in normal lymphoid organ development.
Christine Moussion - One of the best experts on this subject based on the ideXlab platform.
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dendritic cells control lymphocyte entry to lymph nodes through high endothelial venules
Nature, 2011Co-Authors: Christine Moussion, Jeanphilippe GirardAbstract:Christine Moussion and Jean-Philippe Girard report that dendritic cells in the immune system have an unexpected immune surveillance role in lymphocyte recirculation during homeostasis. Lymphotoxin ligands derived from dendritic cells promote the growth of high endothelial venules — blood vessels specialized in lymphocyte recruitment — which control the entry of naive lymphocytes from the blood into lymph nodes. While patrolling the body in search of foreign antigens, naive lymphocytes continuously circulate from the blood, through the lymph nodes, into the lymphatic vessels and back to the blood1,2. This process, called lymphocyte recirculation, provides the body with effective immune surveillance for foreign invaders and for alterations to the body’s own cells. However, the mechanisms that regulate lymphocyte recirculation during homeostasis remain incompletely characterized. Here we show that dendritic cells (DCs), which are well known for their role in antigen presentation to T lymphocytes3, control the entry of naive lymphocytes to lymph nodes by modulating the phenotype of high endothelial venules (HEVs), which are blood vessels specialized in lymphocyte recruitment2,4,5. We found that in vivo depletion of CD11c+ DCs in adult mice over a 1-week period induces a reduction in the size and cellularity of the peripheral and mucosal lymph nodes. In the absence of DCs, the mature adult HEV phenotype reverts to an immature neonatal phenotype, and HEV-mediated lymphocyte recruitment to lymph nodes is inhibited. Co-culture experiments showed that the effect of DCs on HEV endothelial cells is direct and requires Lymphotoxin-β-receptor-dependent signalling. DCs express Lymphotoxin, and DC-derived Lymphotoxin is important for lymphocyte homing to lymph nodes in vivo. Together, our results reveal a previously unsuspected role for DCs in the regulation of lymphocyte recirculation during immune surveillance.
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Dendritic cells control lymphocyte entry to lymph nodes through high endothelial venules
Nature, 2011Co-Authors: Christine Moussion, Jeanphilippe GirardAbstract:While patrolling the body in search of foreign antigens, naive lymphocytes continuously circulate from the blood, through the lymph nodes, into the lymphatic vessels and back to the blood. This process, called lymphocyte recirculation, provides the body with effective immune surveillance for foreign invaders and for alterations to the body's own cells. However, the mechanisms that regulate lymphocyte recirculation during homeostasis remain incompletely characterized. Here we show that dendritic cells (DCs), which are well known for their role in antigen presentation to T lymphocytes, control the entry of naive lymphocytes to lymph nodes by modulating the phenotype of high endothelial venules (HEVs), which are blood vessels specialized in lymphocyte recruitment. We found that in vivo depletion of CD11c(+) DCs in adult mice over a 1-week period induces a reduction in the size and cellularity of the peripheral and mucosal lymph nodes. In the absence of DCs, the mature adult HEV phenotype reverts to an immature neonatal phenotype, and HEV-mediated lymphocyte recruitment to lymph nodes is inhibited. Co-culture experiments showed that the effect of DCs on HEV endothelial cells is direct and requires Lymphotoxin-β-receptor-dependent signalling. DCs express Lymphotoxin, and DC-derived Lymphotoxin is important for lymphocyte homing to lymph nodes in vivo. Together, our results reveal a previously unsuspected role for DCs in the regulation of lymphocyte recirculation during immune surveillance.
Torsten Kucharzik - One of the best experts on this subject based on the ideXlab platform.
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the Lymphotoxin β receptor is critical for control of murine citrobacter rodentium induced colitis
Gastroenterology, 2004Co-Authors: Thomas W. Spahn, Christian Maaser, Lars Eckmann, Jan Heidemann, Andreas Lügering, Rodney D. Newberry, Wolfram Domschke, Hermann Herbst, Torsten KucharzikAbstract:Background & Aims: Lymphotoxin is a tumor necrosis factor-family cytokine. Blocking of Lymphotoxin α 1 β 2 /Lymphotoxin-β receptor interactions prevents experimental colitis in mice, and this suggests a potential treatment principle of human inflammatory bowel disease. Infection of mice with Citrobacter rodentium serves as an animal model for human infectious colitis induced by enteropathogenic Escherichia coli . We studied the role of Lymphotoxin α 1 β 2 /Lymphotoxin-β receptor signaling in Citrobacter rodentium –induced colitis. Methods: Mice with disrupted Lymphotoxin α 1 β 2 /Lymphotoxin-β receptor interactions secondary to gene defects (Lymphotoxin-α −/− , Lymphotoxin-β −/− , and Lymphotoxin-β receptor −/− ) or treatment with the antagonist Lymphotoxin-β receptor-immunoglobulin G fusion protein were infected with Citrobacter rodentium . Body weight, fecal excretion of Citrobacter rodentium , and disease-related mortality were monitored. Spleen and liver organ cultures of mice assessed systemic infection. Intestinal inflammation and lymphoid architecture were histologically recorded in the large intestine, mesenteric lymph nodes, and spleen of infected mice. Results: Inhibition of Lymphotoxin α 1 β 2 /Lymphotoxin-β receptor interactions was associated with increased severity of Citrobacter rodentium –induced colitis, as indicated by increased disease-related mortality, more severe weight loss, intestinal bacterial abscesses, and a higher burden of Citrobacter rodentium in the spleen and liver of −/− and Lymphotoxin-β receptor-immunoglobulin G-treated mice. There was a reduction of CD11c + dendritic cells in the spleen of naive and infected −/− and Lymphotoxin-β receptor-immunoglobulin G-treated mice. In infected Lymphotoxin-β receptor −/− mice, anti– Citrobacter rodentium immunoglobulin G2a levels were decreased, whereas immunoglobulin G1 levels were increased. Citrobacter rodentium –induced interleukin-4 secretion was increased in Lymphotoxin-β receptor −/− mice. Conclusions: Lymphotoxin α 1 β 2 /Lymphotoxin-β receptor interactions are critical for immunity against Citrobacter rodentium in mice. Impaired anti-enteropathogenic Escherichia coli immunity may be anticipated in anti-Lymphotoxin-β receptor-directed therapy for human inflammatory bowel disease.
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induction of colitis in mice deficient of peyer s patches and mesenteric lymph nodes is associated with increased disease severity and formation of colonic lymphoid patches
American Journal of Pathology, 2002Co-Authors: Thomas W. Spahn, Christian Maaser, Wolfram Domschke, Hermann Herbst, Adriano Fontana, Paul D Rennert, N Lugering, Mathias Kraft, Howard L Weiner, Torsten KucharzikAbstract:Inflammatory bowel disease is associated with immune activation in Peyer's patches and mucosal lymph nodes. The role of these organs in dextran sodium sulfate (DSS)-induced colitis was investigated. We used mice lacking Peyer's patches and/or lymph nodes because of Lymphotoxin-α gene deficiency or treatment in utero with Lymphotoxin-β-receptor IgG and tumor necrosis factor-receptor-I (55)-IgG fusion proteins. Mice lacking Peyer's patches and lymph nodes because of Lymphotoxin-α deficiency or in utero fusion protein treatment developed more severe colitis than control mice as indicated by more severe intestinal shrinking, longer colonic ulcers, and higher histological disease scores. Oral DSS triggered the formation of colonic submucosal lymphoid patches in these mice and caused an increase in the number of submucosal lymphoid patches in mice treated in utero with the fusion proteins. Mice lacking Peyer's patches only showed more submucosal lymphoid patches whereas intestinal length and histological disease score were similar to control mice. In conclusion, more severe DSS-induced colitis correlates with the loss of the mesenteric lymph nodes. However, neither the absence of Peyer's patches nor the presence of colonic lymphoid patches were correlated with increased disease severity.
