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Jeanphilippe Girard - One of the best experts on this subject based on the ideXlab platform.
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High Endothelial Venules (HEVs) in immunity, inflammation and cancer
Angiogenesis, 2021Co-Authors: Lucas Blanchard, Jeanphilippe GirardAbstract:High Endothelial Venules (HEVs) are specialized blood vessels mediating lymphocyte trafficking to lymph nodes (LNs) and other secondary lymphoid organs. By supporting High levels of lymphocyte extravasation from the blood, HEVs play an essential role in lymphocyte recirculation and immune surveillance for foreign invaders (bacterial and viral infections) and alterations in the body’s own cells (neoantigens in cancer). The HEV network expands during inflammation in immune-stimulated LNs and is profoundly remodeled in metastatic and tumor-draining LNs. HEV-like blood vessels expressing High levels of the HEV-specific sulfated MECA-79 antigens are induced in non-lymphoid tissues at sites of chronic inflammation in many human inflammatory and allergic diseases, including rheumatoid arthritis, Crohn’s disease, allergic rhinitis and asthma. Such vessels are believed to contribute to the amplification and maintenance of chronic inflammation. MECA-79^+ tumor-associated HEVs (TA-HEVs) are frequently found in human tumors in CD3^+ T cell-rich areas or CD20^+ B-cell rich tertiary lymphoid structures (TLSs). TA-HEVs have been proposed to play important roles in lymphocyte entry into tumors, a process essential for successful antitumor immunity and lymphocyte-mediated cancer immunotherapy with immune checkpoint inhibitors, vaccines or adoptive T cell therapy. In this review, we Highlight the phenotype and function of HEVs in homeostatic, inflamed and tumor-draining lymph nodes, and those of HEV-like blood vessels in chronic inflammatory diseases. Furthermore, we discuss the role and regulation of TA-HEVs in human cancer and mouse tumor models.
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Single-Cell Analysis Reveals Heterogeneity of High Endothelial Venules and Different Regulation of Genes Controlling Lymphocyte Entry to Lymph Nodes
Elsevier, 2019Co-Authors: Krystle Veerman, Claire Tardiveau, Frédéric Martins, Juliette Coudert, Jeanphilippe GirardAbstract:Summary: High-Endothelial Venules (HEVs) are specialized blood vessels allowing recirculation of naive lymphocytes through lymphoid organs. Here, using full-length, single-cell RNA sequencing, RNA fluorescence in situ hybridization (FISH), flow cytometry, and immunohistofluorescence, we reveal the heterogeneity of HEVs in adult mouse peripheral lymph nodes (PLNs) under conditions of homeostasis, antigenic stimulation, and after inhibition of lymphotoxin-β receptor (LTβR) signaling. We demonstrate that HEV Endothelial cells are in an activated state during homeostasis, and we identify the genes characteristic of the differentiated HEV phenotype. We show that LTβR signaling regulates many HEV genes and pathways in resting PLNs and that immune stimulation induces a global and temporary inflammatory phenotype in HEVs without compromising their ability to recruit naive lymphocytes. Most importantly, we uncover differences in the regulation of genes controlling lymphocyte trafficking, Glycam1, Fut7, Gcnt1, Chst4, B3gnt3, and Ccl21a, that have implications for HEV function and regulation in health and disease. : High-Endothelial Venules (HEVs) are specialized blood vessels that allow lymphocyte recirculation through the different lymphoid organs of the body. Using single-cell RNA sequencing, Veerman et al. uncover the cellular and spatial heterogeneity of HEVs in lymph nodes and unveil important differences in the regulation of genes controlling lymphocyte trafficking. Keywords: High-Endothelial venule, peripheral lymph node, Endothelial cell, lymphocyte trafficking, lymphocyte homing, homeostasis, inflammation, single-cell RNA sequencing, scRNA-seq, lymphotoxin-beta recepto
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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.
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human solid tumors contain High Endothelial Venules association with t and b lymphocyte infiltration and favorable prognosis in breast cancer
Cancer Research, 2011Co-Authors: Ludovic Martinet, Ignacio Garrido, Sophie Le Guellec, Thomas Filleron, Philippe Rochaix, Elisabeth Bellard, Jeanjacques Fournie, Jeanphilippe GirardAbstract:The mechanisms governing infiltration of lymphocytes into tumors remain poorly characterized, in spite of the critical impact of these cells on patient prognosis and therapeutic responses. High Endothelial Venules (HEV) are blood vessels found in lymphoid tissues, specialized in lymphocyte recruitment, but their implications in human cancer are unknown. In this article, we report the presence of MECA 79(+) blood vessels displaying all the phenotypic characteristics of HEVs in most of the 319 human primary solid tumors, including melanomas, breast, ovarian, colon, and lung carcinomas, analyzed. Tumor HEVs were specifically located within lymphocyte-rich areas, and their density within the tumor stroma was a strong predictor of infiltration by CD3(+) and CD8(+) T cells as well as B cells. Large-scale flow cytometric and quantitative reverse transcriptase-PCR analyses in freshly operated breast tumors revealed that High densities of tumor HEVs correlated with increased naive, central memory and activated effector memory T-cell infiltration and upregulation of genes related to T-helper 1 adaptive immunity and T-cell cytotoxicity. Finally, in a retrospective cohort of 146 invasive breast cancer patients, we found that High densities of tumor HEVs independently conferred a lower risk of relapse and significantly correlated with longer metastasis-free, disease-free, and overall survival rates. Together, our findings suggest that tumor HEVs function as major gateways for lymphocyte infiltration into human tumors, and may represent attractive targets for cancer diagnosis and therapy.
J Girard - One of the best experts on this subject based on the ideXlab platform.
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single cell analysis reveals heterogeneity of High Endothelial Venules and different regulation of genes controlling lymphocyte entry to lymph nodes
Cell Reports, 2019Co-Authors: Krystle Veerman, Claire Tardiveau, Frédéric Martins, Juliette Coudert, J GirardAbstract:High-Endothelial Venules (HEVs) are specialized blood vessels allowing recirculation of naive lymphocytes through lymphoid organs. Here, using full-length, single-cell RNA sequencing, RNA fluorescence in situ hybridization (FISH), flow cytometry, and immunohistofluorescence, we reveal the heterogeneity of HEVs in adult mouse peripheral lymph nodes (PLNs) under conditions of homeostasis, antigenic stimulation, and after inhibition of lymphotoxin-β receptor (LTβR) signaling. We demonstrate that HEV Endothelial cells are in an activated state during homeostasis, and we identify the genes characteristic of the differentiated HEV phenotype. We show that LTβR signaling regulates many HEV genes and pathways in resting PLNs and that immune stimulation induces a global and temporary inflammatory phenotype in HEVs without compromising their ability to recruit naive lymphocytes. Most importantly, we uncover differences in the regulation of genes controlling lymphocyte trafficking, Glycam1, Fut7, Gcnt1, Chst4, B3gnt3, and Ccl21a, that have implications for HEV function and regulation in health and disease.
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abstract b156 tumor High Endothelial Venules hevs specialized blood vessels which recruit lymphocytes to limit tumor progression
Cancer immunology research, 2016Co-Authors: Robin Laffont, Fanny Lafouresse, J GirardAbstract:We discovered that some blood vessels present within the tumor microenvironment can be associated with favorable prognosis by contributing to tumor suppression rather than tumor growth (Martinet and Girard, Cancer Res 2011). These specialized blood vessels, designated High Endothelial Venules (HEVs), are normally found in lymph nodes where they mediate lymphocyte entry (Girard et al., Nat Rev Immunol 2012). A High density of tumor HEVs in human tumors was associated with High levels of cytotoxic lymphocyte infiltration, indicating that HEVs may contribute to the eradication of tumors by facilitating access of ‘killer’ lymphocytes into tumor tissues. It is thus important to better define the mechanisms regulating HEV formation. Our previous data have revealed a critical role for dendritic cells (Moussion and Girard, Nature 2011). Here, we will present our most recent results indicating that tumor HEVs may be central to the control of tumor growth in mouse tumor models. Citation Format: Robin Laffont, Fanny Lafouresse, Jean-Philippe Girard. Tumor High Endothelial Venules (HEVs), specialized blood vessels which recruit lymphocytes to limit tumor progression. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B156.
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tumor High Endothelial Venules and lymphocyte trafficking
2014Co-Authors: Krystle M Veerman, Fanny Lafouresse, J GirardAbstract:Blood vessels and tumor angiogenesis are generally associated with tumor growth and poor clinical outcome of cancer patients. However, it has been recently discovered that some blood vessels present within the tumor microenvironment can be associated with a good prognosis by contributing to tumor suppression rather than tumor growth. These specialized blood vessels, designated High Endothelial Venules (HEVs), are normally found in lymph nodes where they mediate High levels of lymphocyte extravasation from the blood. A High density of tumor HEVs in human breast carcinomas and melanomas was associated with High levels of cytotoxic lymphocyte infiltration, indicating that HEVs may participate in the eradication of tumors by facilitating the access of “killer” lymphocytes into tumor tissues. A better understanding of the mechanisms regulating tumor HEVs could thus have an important impact for cancer therapy. Dendritic cells and the lymphotoxin pathway have been shown to be critical for maintenance of HEV differentiation in lymph nodes and may also regulate tumor HEVs. In this chapter, we will first describe the unique properties of lymph node HEVs and their role in lymphocyte trafficking. We will then review the phenotypic characteristics of tumor HEVs and their association with lymphocyte infiltration and favorable clinical outcome of cancer patients. Finally, we will discuss the promising potential of tumor HEVs for cancer therapy.
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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, J 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 Venules hevs in human melanoma lesions major gateways for tumor infiltrating lymphocytes
OncoImmunology, 2012Co-Authors: Ludovic Martinet, Ignacio Garrido, Sophie Le Guellec, Thomas Filleron, Laurence Lamant, Nicolas Meyer, Philippe Rochaix, J GirardAbstract:The presence of tumor-infiltrating lymphocytes (TILs) is a strong prognostic parameter for local dissemination and overall survival in melanoma. Lymphocyte migration from blood into peripheral tissues is mainly regulated by vascular endothelium. However, the blood vessels and mechanisms governing the recruitment of TILs in melanoma tumors remain poorly understood. Here, we show that High Endothelial Venules (HEVs), specialized blood vessels for lymphocyte extravasation into lymphoid tissues, are frequently found in melanoma tumors and are associated with High levels of lymphocyte infiltration. The analysis of 225 primary melanomas revealed that lymphocytes specifically infiltrated HEV-rich areas of melanoma tumors and that the density of MECA-79+ HEVs was variable among patients and strongly correlated with CD3+, CD8+ and CD20+ TIL densities. Inflammatory (CCL5, CXCL9, CXCL10 and CXCL11) and lymphoid (CCL21, CCL19 and CXCL13) chemokines as well as TH1 and naive T-cell genes were overexpressed in melanoma samples with High densities of tumor HEVs. Mature dendritic cells (mDCs) were frequently found around tumor HEVs and densities of HEVs and DC-LAMP+ mDCs within tumor stroma were strongly correlated. DCs which maintain HEVs in lymph nodes, may thus also contribute to the regulation of HEVs in melanomas. Finally, we found significantly Higher densities of tumor HEVs in melanomas with tumor regression, low Clark level of invasion and thin Breslow thickness (all p < 0.001). The strong association between tumor HEVs, TILs, mDCs and clinical parameters of melanoma, supports a critical role for HEVs in limiting malignant melanoma development through both naive and effector T-lymphocyte recruitment and activation.
Ann Ager - One of the best experts on this subject based on the ideXlab platform.
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High Endothelial Venules are associated with microsatellite instability, hereditary background and immune evasion in colorectal cancer
British Journal of Cancer, 2019Co-Authors: Pauline L. Pfuderer, Ann Ager, Alexej Ballhausen, Florian Seidler, Hans-jürgen Stark, Niels Grabe, Ian M. Frayling, Magnus Knebel Doeberitz, Matthias Kloor, Aysel AhadovaAbstract:Background Microsatellite-unstable (MSI) tumours show a High load of mutational neo antigens, as a consequence of DNA mismatch repair deficiency. Consequently, MSI tumours commonly present with dense immune infiltration and develop immune evasion mechanisms. Whether improved lymphocyte recruitment contributes to the pronounced immune infiltration in MSI tumours is unknown. We analysed the density of High Endothelial Venules (HEV) and postcapillary blood vessels specialised for lymphocyte trafficking, in MSI colorectal cancers (CRC). Methods HEV density was determined by immunohistochemical staining of FFPE tissue sections from MSI ( n = 48) and microsatellite-stable (MSS, n = 35) CRCs. Associations with clinical and pathological variables were analysed. Results We found elevated HEV densities in MSI compared with MSS CRCs (median 0.049 vs 0.000 counts/mm^2, respectively, p = 0.0002), with the Highest densities in Lynch syndrome MSI CRCs. Dramatically elevated HEV densities were observed in B2M- mutant Lynch syndrome CRCs, pointing towards a link between lymphocyte recruitment and immune evasion (median 0.485 vs 0.0885 counts/mm^2 in B2M -wild-type tumours, p = 0.0237). Conclusions Our findings for the first time indicate a significant contribution of lymphocyte trafficking in immune responses against MSI CRC, particularly in the context of Lynch syndrome. High HEV densities in B2M -mutant tumours underline the significance of immunoediting during tumour evolution.
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Defining High Endothelial Venules and Tertiary Lymphoid Structures in Cancer.
Methods in molecular biology (Clifton N.J.), 2018Co-Authors: Emma Jones, Awen Gallimore, Ann AgerAbstract:High Endothelial Venules (HEVs) are structurally distinct blood vessels that develop during embryonic and neonatal life in all secondary lymphoid organs except the spleen. HEVs are critical for initiating and maintaining immune responses because they extract naive and memory lymphocytes from the bloodstream, regardless of antigen receptor specificity, and deliver them to antigen-presenting cells inside lymph nodes under homeostatic conditions. HEVs also develop postnatally in nonlymphoid organs during chronic inflammation driven by autoimmunity, infection, allografts, and cancer. Extranodal HEVs are usually surrounded by dense lymphocytic infiltrates organized into lymph-node like, T- and B-cell-rich areas called tertiary lymphoid structures (TLS). HEV neogenesis is thought to facilitate the generation of tissue-destroying lymphocytes inside chronically inflamed tissues and cancers.We are studying the mechanisms underpinning HEV neogenesis in solid cancers and the role of homeostatic T-cell trafficking in controlling cancer immunity. In this chapter we describe methods for identifying HEV in tissue sections of cancerous tissues in humans and mice using immunohistochemical staining for the HEV-specific marker peripheral lymph node addressin (PNAd). L-selectin binding to PNAd is a necessary first step in homeostatic lymphocyte trafficking which is the defining function of HEV. We also describe methods to measure L-selectin-dependent homing of lymphocytes from the bloodstream into lymphoid tissues and tumors in preclinical cancer models.
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High Endothelial Venules and other blood vessels critical regulators of lymphoid organ development and function
Frontiers in Immunology, 2017Co-Authors: Ann AgerAbstract:The blood vasculature regulates both the development and function of secondary lymphoid organs by providing a portal for entry of hemopoietic cells. During the development of lymphoid organs in the embryo, blood vessels deliver lymphoid tissue inducer cells that initiate and sustain the development of lymphoid tissues. In adults, the blood vessels are structurally distinct from those in other organs due to the requirement for High levels of lymphocyte recruitment under non-inflammatory conditions. In lymph nodes (LNs) and Peyer's patches, High Endothelial Venules (HEVs) especially adapted for lymphocyte trafficking form a spatially organized network of blood vessels, which controls both the type of lymphocyte and the site of entry into lymphoid tissues. Uniquely, HEVs express vascular addressins that regulate lymphocyte entry into lymphoid organs and are, therefore, critical to the function of lymphoid organs. Recent studies have demonstrated important roles for CD11c+ dendritic cells in the induction, as well as the maintenance, of vascular addressin expression and, therefore, the function of HEVs. Tertiary lymphoid organs (TLOs) are HEV containing LN-like structures that develop inside organized tissues undergoing chronic immune-mediated inflammation. In autoimmune lesions, the development of TLOs is thought to exacerbate disease. In cancerous tissues, the development of HEVs and TLOs is associated with improved patient outcomes in several cancers. Therefore, it is important to understand what drives the development of HEVs and TLOs and how these structures contribute to pathology. In several human diseases and experimental animal models of chronic inflammation, there are some similarities between the development and function of HEVs within LN and TLOs. This review will summarize current knowledge of how hemopoietic cells with lymphoid tissue-inducing, HEV-inducing, and HEV-maintaining properties are recruited from the bloodstream to induce the development and control the function of lymphoid organs.
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understanding High Endothelial Venules lessons for cancer immunology
OncoImmunology, 2015Co-Authors: Ann Ager, Michael J MayAbstract:High Endothelial Venules (HEVs) are blood vessels especially adapted for lymphocyte trafficking which are normally found in secondary lymphoid organs such as lymph nodes (LN) and Peyer's patches. It has long been known that HEVs develop in non-lymphoid organs during chronic inflammation driven by autoimmunity, infection or allografts. More recently, HEVs have been observed in solid, vascularized tumors and their presence correlated with reduced tumor size and improved patient outcome. It is proposed that newly formed HEV promote antitumor immunity by recruiting naive lymphocytes into the tumor, thus allowing the local generation of cancerous tissue-destroying lymphocytes. Understanding how HEVs develop and function are therefore important to unravel their role in human cancers. In LN, HEVs develop during embryonic and early post-natal life and are actively maintained by the LN microenvironment. Systemic blockade of lymphotoxin-β receptor leads to HEV de-differentiation, but the LN components that induce HEV differentiation have remained elusive. Recent elegant studies using gene-targeted mice have demonstrated clearly that triggering the lymphotoxin-β receptor in Endothelial cells (EC) induces the differentiation of HEV and that CD11c+ dendritic cells play a crucial role in this process. It will be important to determine whether lymphotoxin-β receptor-dependent signaling in EC drives the development of HEV during tumorigenesis and which cells have HEV-inducer properties. This may reveal therapeutic approaches to promote HEV neogenesis and determine the impact of newly formed HEV on tumor immunity.
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High Endothelial Venules are rare in colorectal cancers but accumulate in extra tumoral areas with disease progression
OncoImmunology, 2015Co-Authors: Diana Filipa Costa Bento, Emma Jones, Ann Ager, Andrew James Godkin, Syed Junaid, Justyna Tull, Geraint T Williams, Awen GallimoreAbstract:Prolonged patient survival after surgical resection, is associated with a Higher cytotoxic and memory T cell density within colorectal cancers (CRC). High Endothelial Venules (HEVs) are specialized blood vessels present in secondary lymphoid organs (SLO) that allow ingress of naive and central memory T cells from the blood. It has been proposed that HEVs in tumors might serve as a similar route of entry for lymphocytes into the tumor and result in an improved prognosis. The present study aimed to characterize HEVs and their microenvironment in resected tumors from colorectal cancer patients (n = 62). We observed HEVs in association with lymphoid aggregates in 49 out of 62 patients. However, these HEV+ lymphoid aggregates were largely at the invasive margin of the tumor and although there was an association with lymphocytes and HEVs at the invasive margin (p = 0.002) there was only a very weak association with tumor infiltrating lymphocytes. Indeed, lymphoid aggregates were associated with more advanced disease (Dukes’ stage C) and did not indicate a favorable prognosis.
Christine Moussion - One of the best experts on this subject based on the ideXlab platform.
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l selectin controls trafficking of chronic lymphocytic leukemia cells in lymph node High Endothelial Venules in vivo
Blood, 2015Co-Authors: Christine Moussion, Fanny Lafouresse, Elisabeth Bellard, Camille Laurent, Jeanjacques Fournie, Loic YsebaertAbstract:B-cell chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Lymph nodes (LNs) are sites of malignant proliferation and LN enlargement is associated with poor prognosis in the clinics. The LN microenvironment is believed to favor disease progression by promoting CLL cell growth and drug resistance. A better understanding of the mechanisms regulating trafficking of CLL cells to LNs is thus urgently needed. Here, we studied the first step of CLL cell migration to LNs, their interaction with High Endothelial Venules (HEVs), specialized blood vessels for lymphocyte extravasation in lymphoid organs. We observed that the density of HEV blood vessels was increased in CLL LNs and that CD20(+) CLL cells accumulated within HEV pockets, suggesting intense trafficking. We used intravital imaging to visualize the behavior of human CLL cells within the mouse LN microcirculation, and discovered that CLL cells bind to HEVs in vivo via a multistep adhesion cascade, which involves rolling, sticking, and crawling of the leukemic cells on the endothelium. Functional analyses revealed that the lymphocyte homing receptor L-selectin (CD62L) is the key factor controlling the binding of CLL cells to HEV walls in vivo. Interestingly, L-selectin expression was decreased on CLL cells from patients treated with idelalisib, a phosphoinositide-3-kinase δ inhibitor recently approved for CLL therapy. Interference with L-selectin-mediated trafficking in HEVs could represent a novel strategy to block dissemination of CLL cells to LNs and increase the efficacy of conventional therapy.
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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.
Espen S Baekkevold - One of the best experts on this subject based on the ideXlab platform.
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Brief Definitive Report The CCR7 Ligand ELC (CCL19) Is Transcytosed in High Endothelial Venules and Mediates T Cell Recruitment
2020Co-Authors: Espen S Baekkevold, Ulrich H Von Andrian, Hege S Carlsen, Per Brandtzaeg, Takeshi Yamanaka, Roger T Palframan, Finn P Reinholt, Guttorm HaraldsenAbstract:Abstract Lymphocyte homing to secondary lymphoid tissue is defined by a multistep sequence of interactions between lymphocytes and Endothelial cells in High Endothelial Venules (HEVs). After initial selectin-mediated tethering and rolling, firm adhesion of lymphocytes requires rapid upregulation of lymphocyte integrin adhesiveness. This step is mediated in part by the HEVderived chemokine SLC (secondary lymphoid-tissue chemokine, or CCL21) that binds to the CC chemokine receptor (CCR)7 on lymphocytes. However, the CC chemokine ELC (EpsteinBarr virus-induced molecule 1 ligand chemokine, or CCL19) shares the same receptor, and ELC transcripts have been observed in the T cell areas of lymphoid organs. Here, we show that perivascular ELC is transcytosed to the luminal surfaces of HEVs and enables efficient T cell homing to lymph nodes. In situ hybridization on sections of human tonsil showed no ELC mRNA in HEVs, but immunostaining revealed ELC protein in cytoplasmic vesicles of HEV cells. Furthermore, ELC injected into the footpads of mice entered the draining lymph nodes and was presented by HEVs. Finally, intracutaneous injections of ELC in mice lacking functionally relevant ELC and SLC ( plt/plt mice) restored T cell trafficking to draining lymph nodes as efficiently as SLC. We conclude that perivascular ELC is transcytosed to the luminal surfaces of HEVs and participates in CCR7-mediated triggering of lymphocyte arrest
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disparate lymphoid chemokine expression in mice and men no evidence of ccl21 synthesis by human High Endothelial Venules
Blood, 2005Co-Authors: Hege S Carlsen, Guttorm Haraldsen, Per Brandtzaeg, Espen S BaekkevoldAbstract:T-cell homing to secondary lymphoid tissues generally depends on chemokine-induced firm adhesion in High Endothelial Venules (HEVs) and is primarily mediated through the CC chemokine receptor 7 (CCR7) on lymphocytes. The CCR7 ligand designated CCL21 is considered the most important trigger because it appears constitutively expressed by murine HEVs. Surprisingly, when we analyzed human tissues, no CCL21 mRNA could be detected in HEVs. In fact, CCL21 mRNA was only expressed in extravascular T-zone cells and lymphatics, whereas immunostaining revealed CCL21 protein within HEVs. This suggests that T-cell recruitment to human lymphoid tissues depends on the transcytosis of lymphoid chemokines through HEV cells because there is at present no evidence of alternative chemokine production in these cells that could explain the attraction of naive T lymphocytes.
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the ccr7 ligand elc ccl19 is transcytosed in High Endothelial Venules and mediates t cell recruitment
Journal of Experimental Medicine, 2001Co-Authors: Espen S Baekkevold, Ulrich H Von Andrian, Hege S Carlsen, Per Brandtzaeg, Takeshi Yamanaka, Roger T Palframan, Finn P Reinholt, Guttorm HaraldsenAbstract:Lymphocyte homing to secondary lymphoid tissue is defined by a multistep sequence of interactions between lymphocytes and Endothelial cells in High Endothelial Venules (HEVs). After initial selectin-mediated tethering and rolling, firm adhesion of lymphocytes requires rapid upregulation of lymphocyte integrin adhesiveness. This step is mediated in part by the HEV-derived chemokine SLC (secondary lymphoid-tissue chemokine, or CCL21) that binds to the CC chemokine receptor (CCR)7 on lymphocytes. However, the CC chemokine ELC (Epstein-Barr virus–induced molecule 1 ligand chemokine, or CCL19) shares the same receptor, and ELC transcripts have been observed in the T cell areas of lymphoid organs. Here, we show that perivascular ELC is transcytosed to the luminal surfaces of HEVs and enables efficient T cell homing to lymph nodes. In situ hybridization on sections of human tonsil showed no ELC mRNA in HEVs, but immunostaining revealed ELC protein in cytoplasmic vesicles of HEV cells. Furthermore, ELC injected into the footpads of mice entered the draining lymph nodes and was presented by HEVs. Finally, intracutaneous injections of ELC in mice lacking functionally relevant ELC and SLC ( plt/plt mice) restored T cell trafficking to draining lymph nodes as efficiently as SLC. We conclude that perivascular ELC is transcytosed to the luminal surfaces of HEVs and participates in CCR7-mediated triggering of lymphocyte arrest.
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heterogeneity of Endothelial cells the specialized phenotype of human High Endothelial Venules characterized by suppression subtractive hybridization
American Journal of Pathology, 1999Co-Authors: Jeanphilippe Girard, Espen S Baekkevold, Guttorm Haraldsen, Per Brandtzaeg, Takeshi Yamanaka, François AmalricAbstract:High Endothelial Venules (HEVs) are specialized postcapillary Venules, found in lymphoid organs and chronically inflamed tissues, that support High levels of lymphocyte extravasation from the blood. Molecular characterization of HEV Endothelial cells (HEVECs) has been hampered by difficulties in their purification and in vitro maintenance. To overcome these limitations, we developed a strategy combining the use of freshly purified HEVECs (∼98% positive for the HEV-specific marker MECA-79) and the recently described polymerase chain reaction (PCR)-based cDNA subtraction cloning procedure called suppression subtractive hybridization (SSH). Subtracted probes prepared by SSH from small amounts of total RNA were used to screen a HEVEC cDNA library. This resulted in cloning of 22 cDNAs preferentially expressed in HEVECs, which encode the promiscuous chemokine receptor DARC, mitochondrial components, and matricellular proteins. The latter included hevin, thrombospondin-1, and mac25/IGFBP-rP1, which is a secreted growth factor-binding protein previously found to accumulate specifically in tumor blood vessels. Biochemical and histochemical analysis confirmed the identification of mac25 and DARC as novel markers of the HEVECs. Ultrastructural immunolocalization revealed a noticeable association of mac25 and MECA-79 antigens with microvillous processes near the Endothelial cell junctions, suggesting a role for mac25 in the control of lymphocyte emigration. This study shows that PCR-based SSH is useful for cloning of differentially expressed genes in very small samples.
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molecular cloning and functional analysis of sut 1 a sulfate transporter from human High Endothelial Venules
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: J Girard, Espen S Baekkevold, Per Brandtzaeg, Jacques Feliu, François AmalricAbstract:Abstract High Endothelial Venules (HEV) are specialized postcapillary Venules found in lymphoid organs and chronically inflamed tissues that support High levels of lymphocyte extravasation from the blood. One of the major characteristics of HEV Endothelial cells (HEVEC) is their capacity to incorporate large amounts of sulfate into sialomucin-type counter-receptors for the lymphocyte homing receptor L-selectin. Here, we show that HEVEC express two functional classes of sulfate transporters defined by their differential sensitivity to the anion-exchanger inhibitor 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS), and we report the molecular characterization of a DIDS-resistant sulfate transporter from human HEVEC, designated SUT-1. SUT-1 belongs to the family of Na+-coupled anion transporters and exhibits 40–50% amino acid identity with the rat renal Na+/sulfate cotransporter, NaSi-1, as well as with the human and rat Na+/dicarboxylate cotransporters, NaDC-1/SDCT1 and NaDC-3/SDCT2. Functional expression studies in cRNA-injected Xenopus laevis oocytes showed that SUT-1 mediates High levels of Na+-dependent sulfate transport, which is resistant to DIDS inhibition. The SUT-1 gene mapped to human chromosome 7q33. Northern blotting analysis revealed that SUT-1 exhibits a Highly restricted tissue distribution, with abundant expression in placenta. Reverse transcription–PCR analysis indicated that SUT-1 and the diastrophic dysplasia sulfate transporter (DTD), one of the two known human DIDS-sensitive sulfate transporters, are coexpressed in HEVEC. SUT-1 and DTD could correspond, respectively, to the DIDS-resistant and DIDS-sensitive components of sulfate uptake in HEVEC. Together, these results demonstrate that SUT-1 is a distinct human Na+-coupled sulfate transporter, likely to play a major role in sulfate incorporation in HEV.