DOCSLIB.ORG

T-Cell Trafficking Facilitated by High Endothelial Venules Is Required for Tumor Control After Regulatory T-Cell Depletion

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
T-Cell Trafficking Facilitated by High Endothelial Venules Is Required for Tumor Control After Regulatory T-Cell Depletion Published OnlineFirst September 7, 2012; DOI: 10.1158/0008-5472.CAN-12-1912 Cancer Microenvironment and Immunology Research T-Cell Trafficking Facilitated by High Endothelial Venules Is Required for Tumor Control after Regulatory T-Cell Depletion James P. Hindley1, Emma Jones1, Kathryn Smart1, Hayley Bridgeman1, Sarah N. Lauder1, Beatrice Ondondo1, Scott Cutting1, Kristin Ladell1, Katherine K. Wynn1, David Withers2, David A. Price1, Ann Ager1, Andrew J. Godkin1, and Awen M. Gallimore1 Abstract The evolution of immune blockades in tumors limits successful antitumor immunity, but the mechanisms underlying this process are not fully understood. Depletion of regulatory T cells (Treg), a T-cell subset that dampens excessive inflammatory and autoreactive responses, can allow activation of tumor-specific T cells. However, cancer immunotherapy studies have shown that a persistent failure of activated lymphocytes to infiltrate tumors remains a fundamental problem. In evaluating this issue, we found that despite an increase in T- cell activation and proliferation following Treg depletion, there was no significant association with tumor growth rate. In contrast, there was a highly significant association between low tumor growth rate and the extent of T-cell infiltration. Further analyses revealed a total concordance between low tumor growth rate, high T-cell infiltration, and the presence of high endothelial venules (HEV). HEV are blood vessels normally found in secondary lymphoid tissue where they are specialized for lymphocyte recruitment. Thus, our findings suggest that Treg depletion may promote HEV neogenesis, facilitating increased lymphocyte infiltration and destruction of the tumor tissue. These findings are important as they point to a hitherto unidentified role of Tregs, the manipulation of which may refine strategies for more effective cancer immunotherapy. Cancer Res; 72(21); 5473–82. Ó2012 AACR. þ Introduction CD8 T-cell response and slower tumor growth. Use of the þ þ þ Several laboratories have shown that CD4 CD25 Foxp3 DTR-Foxp3 transgenic mice has also shown that Treg deple- regulatory T cells (Treg), which normally serve to control tion can prevent development and even limit the progression of fl tumors induced by the carcinogen methylcholanthrene (MCA) autoimmunity and in ammation, also inhibit immune þ responses to tumor antigens (1). Thus, strategies aimed at in a manner that is dependent on CD8 T cells and IFNg (8). boosting antitumor responses, through manipulation of Tregs, The success of these interventions however remains sub- are being intensely investigated. In mice, prophylactic deple- optimal. Treg depletion, even when combined with vaccina- tion of Tregs using CD25-specific antibodies can limit and tion, does not readily result in the elimination of established even prevent tumor development and/or progression (2–4). tumors as tumor rejection is often observed in only a pro- The development of transgenic mice expressing the primate portion of treated mice. Several factors, including the extent of þ fi diphtheria toxin receptor (DTR) on Foxp3 cells has allowed T-cell activation and/or tumor in ltration, may account for specific and complete depletion of Tregs by administration of this failure (6). In this study, we set out to identify factors diphtheria toxin (DT; 5). Using the melanoma cell line B16, it limiting the success of antitumor immune responses. For this purpose, we used the MCA chemical carcinogenesis model in has been shown that selective Treg depletion using anti-CD25 DTR antibodies (6) or DT (7) results in activation of a tumor-specific combination with Foxp3 mice (5), to identify the key features that distinguish progressing tumors from those that are controlled after Treg depletion. Our findings clearly Authors' Affiliations: 1Infection and Immunity, School of Medicine, Henry indicate that T-cell infiltration and not the extent of acti- 2 Wellcome Building, Cardiff University, Cardiff, United Kingdom; and MRC vation, is a critical bottleneck to tumor destruction in Treg- Centre for Immune Regulation, Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, depleted animals. Moreover, our extensive immunohisto- United Kingdom chemical analyses of MCA-induced tumors from Treg- Note: Supplementary data for this article are available at Cancer Research replete and Treg-depleted mice revealed that control of Online (http://cancerres.aacrjournals.org/). tumor growth, observed in Treg-depleted mice, was deter- mined by development of high endothelial venules (HEV), J.P. Hindley and E. Jones have contributed equally to this work. specialized blood vessels that alter both the composition Corresponding Author: Awen M. Gallimore, Infection and Immunity, fi School of Medicine, Henry Wellcome Building, Cardiff University, Cardiff, and size of the T-cell in ltrate (9, 10). Overall, these data CF144XN, United Kingdom. Phone: 44-2920-687012; Fax: 44-2920- provide a new perspective on the impact of Treg depletion, 687079; E-mail: [email protected] demonstrating that Tregs control immune responses, not doi: 10.1158/0008-5472.CAN-12-1912 only through limiting immune activation, but also through Ó2012 American Association for Cancer Research. influencing blood vessel differentiation. www.aacrjournals.org 5473 Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 2012 American Association for Cancer Research. Published OnlineFirst September 7, 2012; DOI: 10.1158/0008-5472.CAN-12-1912 Hindley et al. Materials and Methods Immunohistochemistry Paraffin sections. Mice Tumors were collected from DTR fi We are grateful to Professor Alexander Rudensky for sup- Foxp3 mice and xed in neutral buffered formalin and fi plying Foxp3DTR mice. These were backcrossed with C57BL/6 embedded in paraf n. Sections 5 mm in thickness, were cut mice for 5 or more generations and housed in accordance with and mounted on slides, dewaxed in xylene and hydrated UK Home Office regulations. using graded alcohols to tap water. After conducting antigen retrieval, by microwaving in 10 mmol/L Tris, 1 mmol/L EDTA buffer pH9 for 8 minutes, sections were cooled for Tumor induction, DT administration, and tumor 30 minutes and then equilibrated in PBS. Endogenous per- monitoring oxidase activity was quenched with Peroxidase Suppressor DTR Foxp3 mice were injected subcutaneously in the left hind (Thermo Scientific) for 15 minutes and nonspecificantibody leg with 400 mg of 3-MCA (Sigma-Aldrich) in 100 mL of olive oil binding was blocked by incubating sections with 2.5% nor- under general anesthetic as described previously (11). Mice mal horse serum (VectorLabs) in PBS for 30 minutes. Sec- were monitored for tumor development weekly up to 2 months tions were stained overnight at 4C with the following and daily thereafter. Tumor-bearing mice were culled before primary antibodies diluted in 1% bovine serum albumin their tumors reached 1.7 cm in diameter, typically 80 to 150 (BSA) in PBS: rat antiperipheral node addressin (PNAd) days after injection or if tumors caused discomfort. DT (Sigma) antibody (clone MECA-79; Biolegend) and rat anti-Mucosal diluted in PBS was administered intraperitoneally (i.p.) every addressin cell adhesion molecule-1 (MAdCAM-1) antibody other day after tumor detection. (clone MECA-367; Biolegend). Primary antibodies were À1 Tumor growth rate (k, days ) was determined using a stat- detected with anti-rat Immpress (VectorLabs) for 30 min- istical software package Prism 5 (GraphPad) with the following utes and visualized with impact 3,30-diaminobenzidine (Vec- ¼ Â Â equation for exponential growth: Y Y0 exp(k X). Tumor torLabs). Sections were counterstained with haematoxylin, diameter (X, mm) was measured every 2 days using calipers. On dehydrated in an ethanol series, and mounted in distyrene, average, measurements were taken for 12 days for PBS-treated plasticizer, xylene. Photomicrographs were taken using a mice and 17 days for DT-treated mice. Therefore, on average 6 NIKON microscope and digital camera. to 8 measurements were used to calculate tumor growth rate. Frozen sections. Tumors and lymph nodes were collected from Foxp3DTR mice, embedded in optimum cutting temper- Flow cytometry ature compound (OCT; RA Lamb), and snap frozen in liquid Single-cell suspensions of spleens, inguinal lymph nodes, nitrogen. Sections, 5 mm in thickness, were fixed for 10 minutes and tumors were prepared. The inguinal lymph node from the in ice-cold acetone and left to dry at room temperature. Slides tumor (left) side was taken as the tumor-draining lymph node were washed in PBS and blocked with Avidin/Biotin Blocking and the contralateral inguinal lymph node as a nondraining Kit (VectorLabs) and then 2.5% normal horse serum (Vector- lymph node. Labs) in PBS for 30 minutes. Sections were stained overnight at For analysis of intracellular cytokines by flow cytometry, 4C with the following primary antibodies diluted in 1% BSA in single-cell suspensions were stimulated with 20 ng/ml phor- PBS: rat anti-PNAd antibody (clone MECA-79; Biolegend), bol myristate acetate (Sigma-Aldrich) and 1 mg/mL ionomycin Alexa Fluor 488 rat anti-MAdCAM-1 antibody (clone MECA- (Sigma-Aldrich). Cells were incubated at 37 C for a total of 4 367; BioLegend), biotin rat anti-PNAd antibody (clone MECA- hours. After 1 hour, 1 mL/mL of GolgiStop (containing mon- 79; BioLegend), rat anti-CD4 (clone RM4–5; eBioscience), rat ensin; Becton Dickinson) was added to each well. anti-CD8 (clone 53–6.7; eBioscience), fluorescein isothiocya-
Load more

Recommended publications
  • In Sickness and in Health: the Immunological Roles of the Lymphatic System
    International Journal of Molecular Sciences Review In Sickness and in Health: The Immunological Roles of the Lymphatic System Louise A. Johnson MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK; [email protected] Abstract: The lymphatic system plays crucial roles in immunity far beyond those of simply providing conduits for leukocytes and antigens in lymph fluid. Endothelial cells within this vasculature are dis- tinct and highly specialized to perform roles based upon their location. Afferent lymphatic capillaries have unique intercellular junctions for efficient uptake of fluid and macromolecules, while expressing chemotactic and adhesion molecules that permit selective trafficking of specific immune cell subsets. Moreover, in response to events within peripheral tissue such as inflammation or infection, soluble factors from lymphatic endothelial cells exert “remote control” to modulate leukocyte migration across high endothelial venules from the blood to lymph nodes draining the tissue. These immune hubs are highly organized and perfectly arrayed to survey antigens from peripheral tissue while optimizing encounters between antigen-presenting cells and cognate lymphocytes. Furthermore, subsets of lymphatic endothelial cells exhibit differences in gene expression relating to specific func- tions and locality within the lymph node, facilitating both innate and acquired immune responses through antigen presentation, lymph node remodeling and regulation of leukocyte entry and exit. This review details the immune cell subsets in afferent and efferent lymph, and explores the mech- anisms by which endothelial cells of the lymphatic system regulate such trafficking, for immune surveillance and tolerance during steady-state conditions, and in response to infection, acute and Citation: Johnson, L.A.
    [Show full text]
  • Endothelial Venules in a Mucosal Site in Naive Lymphocyte Adhesion to High Primary Role of Peripheral Node Addressin Phenotypic
    Nasal-Associated Lymphoid Tissue: Phenotypic and Functional Evidence for the Primary Role of Peripheral Node Addressin in Naive Lymphocyte Adhesion to High This information is current as Endothelial Venules in a Mucosal Site of October 1, 2021. Keri L. Csencsits, Mark A. Jutila and David W. Pascual J Immunol 1999; 163:1382-1389; ; http://www.jimmunol.org/content/163/3/1382 Downloaded from References This article cites 50 articles, 22 of which you can access for free at: http://www.jimmunol.org/content/163/3/1382.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on October 1, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 1999 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Nasal-Associated Lymphoid Tissue: Phenotypic and Functional Evidence for the Primary Role of Peripheral Node Addressin in Naive Lymphocyte Adhesion to High Endothelial Venules in a Mucosal Site1 Keri L. Csencsits, Mark A. Jutila, and David W.
    [Show full text]
  • High Endothelial Venules and Lymphatic Vessels in Tertiary Lymphoid Organs: Characteristics, Functions, and Regulation
    MINI REVIEW published: 09 November 2016 doi: 10.3389/fimmu.2016.00491 High Endothelial Venules and Lymphatic Vessels in Tertiary Lymphoid Organs: Characteristics, Functions, and Regulation Nancy H. Ruddle* Department of Epidemiology of Microbial Diseases, School of Public Health, Yale University School of Medicine, New Haven, CT, USA High endothelial venules (HEVs) and lymphatic vessels (LVs) are essential for the function of the immune system, by providing communication between the body and lymph nodes (LNs), specialized sites of antigen presentation and recognition. HEVs bring in naïve and central memory cells and LVs transport antigen, antigen-presenting cells, and lymphocytes in and out of LNs. Tertiary lymphoid organs (TLOs) are accumulations of lymphoid and stromal cells that arise and organize at ectopic sites in response to chronic inflammation in autoimmunity, microbial infection, graft rejection, and cancer. TLOs are distinguished from primary lymphoid organs – the thymus and bone marrow, and secondary lymphoid organs (SLOs) – the LNs, spleen, and Peyer’s patches, in that Edited by: they arise in response to inflammatory signals, rather than in ontogeny. TLOs usually Andreas Habenicht, do not have a capsule but are rather contained within the confines of another organ. Ludwig Maximilian University of Their structure, cellular composition, chemokine expression, and vascular and stromal Munich, Germany support resemble SLOs and are the defining aspects of TLOs. T and B cells, antigen- Reviewed by: Ingrid E. Dumitriu, presenting cells, fibroblast reticular cells, and other stromal cells and vascular elements St. George’s University including HEVs and LVs are all typical components of TLOs. A key question is whether of London, UK Olivier Thaunat, the HEVs and LVs play comparable roles and are regulated similarly to those in LNs.
    [Show full text]
  • High Endothelial Venules (Hevs? Are Specialized Postcapillary Venules Found in Lymphoid Tissues That Support High Levels of Lymphocyte Extra- Vasation from the Blood
    High endothelialvenules (HEVs): specialized endotheliumfor lymphocytemigration Jean-Philippe Girard and Timothy A. Springer High endothelial venules (HEVs? are specialized postcapillary venules found in lymphoid tissues that support high levels of lymphocyte extra- vasation from the blood. Here, Jean-Philippe Girard and Timothy Springer highlight the unique properties of HEV endotbelium, discuss the mol- ecular mechanisms controlling HE V specialization and review evidence suggesting that HEVs could play an important role in the patbogenesis of chronic inflammatory diseases. While patrolling the body in search of foreign antigen, The specialized endothelium of HEVs lymphocytes continuously circulate from blood, through Structurd feutures of HEVs lymphoid and other tissues, and back through the lym- The endothelial cells of HEVs have a ‘plump’, al- phatics to the blood. This process, called lymphocyte most cuboidal, appearance very different from the flat recirculation, allows the dissemination of the immune morphology of endothelial cells that line other vessels, response throughout the body, and thereby provides an and are therefore called high endothelial cells by ref- effective immune surveillance for foreign Invaders and erence to their thickness (Fig. 1). Another characteris- alterations in the body’s own cells’J. tic of HIS’s, revealed by light-microscopic examina- The first critical step in lymphocyte migration tion, is the presence of a large number of lymphocytes from circulation into tissue is the adhesion of within their walls. This illustrates the function of HEVs lymphocytes to vascular endothelium. In lymphoid in lymphocyte recruitment, and explains why these ves- organs, lymphocyte adherence and transendothelial sels were implicated in lymphocyte traffic from the time migration occur at specialized postcapillary vascular of their initial description”.
    [Show full text]
  • Lymph Nodes High Endothelial Venule Expansion in Factor A
    B Cell-Derived Vascular Endothelial Growth Factor A Promotes Lymphangiogenesis and High Endothelial Venule Expansion in Lymph Nodes This information is current as of September 26, 2021. Binita Shrestha, Teruto Hashiguchi, Takashi Ito, Naoki Miura, Kazunori Takenouchi, Yoko Oyama, Ko-ichi Kawahara, Salunya Tancharoen, Yuya Ki-i, Noboru Arimura, Narimasa Yoshinaga, Satoshi Noma, Chandan Shrestha, Takao Nitanda, Shinichi Kitajima, Kimiyoshi Arimura, Masahiro Sato, Taiji Sakamoto and Ikuro Downloaded from Maruyama J Immunol 2010; 184:4819-4826; Prepublished online 22 March 2010; doi: 10.4049/jimmunol.0903063 http://www.jimmunol.org/ http://www.jimmunol.org/content/184/9/4819 Supplementary http://www.jimmunol.org/content/suppl/2010/03/22/jimmunol.090306 Material 3.DC1 References This article cites 38 articles, 15 of which you can access for free at: by guest on September 26, 2021 http://www.jimmunol.org/content/184/9/4819.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association of Immunologists, Inc.
    [Show full text]
  • Lymphocyte Recirculation
    Lymphocyte Recirculation Chapter 15 Naïve lymphocytes enter lymph nodes Lymphocyte Migration and from the blood circulation Lymphocytes return Inflammation to blood via the thoracic duct Antigens from infected area go to lymph nodes via the lymphatic system I. Primary Lymphoid II. Secondary - Lymph Nodes -Spleen -MALT Lymphatic vessels Leukocytes are constantly moving between sites where - Collect interstitial fluid and carry antigens may be It (lymph), via a system of encountered: progressively larger vessels, into regional lymph nodes. 1 2 - Spleen (via afferent lymphatic vessels). - Lymph nodes - Other secondary -Lymph leaves the lymph nodes lymphoid tissues via efferent lymphatic vessels, - Other tissues – which eventually drain back especially skin and into the circulatory system (via mucosal surfaces the thoracic duct). 3 Leukocytes accumulate at sites of inflammation 1 CHOICES: Antigen capture: (APC) or 1) If no antigen is present: lymphocytes Macrophages: capture and process particulate routinely enter and leave secondary lymphoid antigens (via phagocytosis) tissues Dendritic cells: capture and process non- 2) If antigen enters the secondary lymphoid particulate antigens (via endocytosis) tissue: Lymphocyte proliferation in response to antigen B cells: capture and process antigens that bind to occurs within the lymphoid tissue. surface BCR (via endocytosis) After several days, antigen-activated lymphocytes begin leaving the lymphoid tissue. Dendritic cells: originate in bone marrow, capture antigen within tissues and transport antigen to secondary lymphoid tissue. Lymphocytes can enter lymphoid tissues in two ways: 1 1) Direct entry into lymph nodes via afferent lymphatics 2) Entry from blood capillaries across specialized endothelial cells (high-walled endothelial cells) present in the postcapillary venules (High Endothelial Venules= HEV) within the secondary 2 lymphoid tissue.
    [Show full text]
  • Histological and Immunohistochemical Analysis of Special Compartments of Palatin Tonsils in Relation to Tonsillar Diseases
    Histological and immunohistochemical.. Zahraa A. Tabou Histological and Immunohistochemical Analysis of Special Compartments of Palatin Tonsils in Relation to Tonsillar Diseases Zahraa A. Tabou*, Professor Abduljabbar Y.AL-Hubaity **, Eklas A.Ali *** *Department of Anatomy, College of Medicine, University of Nineveh, Mosul **Department of Anatomy, College of Medicine, University of Mosul, Mosul ***Department of Pathology, College of Medicine, University of Mosul, Mosul Correspondence: [email protected] (Ann Coll Med Mosul 2019; 41 (2):197-204). Received: 16th, May 2019; Accepted: 1st, Sep. 2019. ABSTRACT Background: The tonsils are lymphoepithelial tissue, it contains specialized lymphoid functional compartments which include the lymphoid follicles, parafollicular areas, crypt epithelium and high endothelial venules, which together have an essential role in the immunological process. These compartments may be altered histomorphologically throughout life time underneath common pathological condition. Aim: The aim of the current study is to evaluate special microstructural functional compartment changes as high endothelial venules, lymphoid follicles, interfollicular and connective tissue areas according to histopathological ground of the palatine tonsils. Methods: one hundred palatine tonsillar samples which were attained from patients suffering from chronic tonsillitis, recurrent tonsillitis and obstructive hypertrophic tonsils were admitted at Al-Jumhuri Teaching Hospital and Al-salaam teaching hospital in Mosul city during the period from February 2018 to February 2019. Age of patients ranged from (2-40) years. Specimens of tissue were directly fixed in 10% formalin then processed. Paraffin sections of 4μm thickness were exposed to routine stain with hematoxylin and eosin, while the studied marker (CD34) was detected by immunohistochemical method using labelled streptavidin- biotin (LSAB/HRP) method.
    [Show full text]
  • The Splenic T Cell Zone Within Lymphocyte Entry Into And
    Fibroblastic Reticular Cells Guide T Lymphocyte Entry into and Migration within the Splenic T Cell Zone This information is current as Marc Bajénoff, Nicolas Glaichenhaus and Ronald N. of September 24, 2021. Germain J Immunol 2008; 181:3947-3954; ; doi: 10.4049/jimmunol.181.6.3947 http://www.jimmunol.org/content/181/6/3947 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2008/08/29/181.6.3947.DC1 Material References This article cites 41 articles, 16 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/181/6/3947.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 24, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Fibroblastic Reticular Cells Guide T Lymphocyte Entry into and Migration within the Splenic T Cell Zone1 Marc Baje´noff,*†‡ Nicolas Glaichenhaus,† and Ronald N.
    [Show full text]
  • Specialized Structure and Metabolic Activities Ofhigh Endothelial Venules
    Immunology 1976 31 455 Specialized structure and metabolic activities of high endothelial venules in rat lymphatic tissues N. D. ANDERSON, A. 0. ANDERSON* & R. G. WYLLIE Departments of Pathology, Medicine and Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland, U.S.A. Received 6 August 1975; accepted for publication 9 February 1976 Summary. Microscopic, histochemical and ultra- moved across the sheath by insinuating themselves structural techniques were used to define character- into gaps between overlapping plates. This composite istics of high endothelial venules (HEV) in rat structure of the HEV wall appeared to facilitate lymphatic tissues. This endothelium contained lymphocyte entry into the node and minimized acetyl esterase and acid hydrolase activities which vascular leakage. were not altered by lymphocyte depletion. No immunoglobulins were detected on luminal surfaces of HEV by fluorescent antibody staining. Only INTRODUCTI ON minor structural differences were seen between HEV within lymph nodes and Peyer's patches. At High endothelial venules (HEV) in lymphatic tissues both sites, high endothelial cells were linked together have been regarded as specialized microvascular by macular junctional complexes and interlocking structures since their original description by Thome basal foot processes. Endothelial cell cytoplasm in 1898. The histological demonstration of numerous moulded about surfaces of lymphocytes migrating lymphocytes in the walls and lumens of these through the venular wall, and flocculant deposits venules lead many investigators (Schumacher, 1899; of basement membrane formed over lymphocytes Schulze, 1925; Hummel, 1935; Dabelow, 1939) to penetrating the basal lamina. The endothelium conclude that HEV were important in the ex- was ensheathed by three to five layers of overlapping change of cells between blood and lymphatic tissues.
    [Show full text]
  • Patches in High Endothelial Venules of Peyer's P-Selectin in Leukocyte Rolling and Adhesion Integrins, and 7Β the Roles of L-Se
    The Roles of L-Selectin, β7 Integrins, and P-Selectin in Leukocyte Rolling and Adhesion in High Endothelial Venules of Peyer's Patches This information is current as of September 25, 2021. Eric J. Kunkel, Carroll L. Ramos, Douglas A. Steeber, Werner Müller, Norbert Wagner, Thomas F. Tedder and Klaus Ley J Immunol 1998; 161:2449-2456; ; http://www.jimmunol.org/content/161/5/2449 Downloaded from References This article cites 44 articles, 23 of which you can access for free at: http://www.jimmunol.org/content/161/5/2449.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 25, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 1998 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. b The Roles of L-Selectin, 7 Integrins, and P-Selectin in Leukocyte Rolling and Adhesion in High Endothelial Venules of Peyer’s Patches1 Eric J. Kunkel,* Carroll L. Ramos,* Douglas A.
    [Show full text]
  • LECTURE 06 Lymphoid System and Location of the Immune Cells
    LECTURE: 06 Title: LYMPHOID SYSTEM & LOCATION OF THE IMMUNE CELLS LEARNING OBJECTIVES: The student should be able to: • Define the term "lymph", lymphoreticular system. • Identify the primary and secondary lymphoid organs. • Explain the primary and secondary lymphoid follicles (Germinal center). • Compare between the follicular dendritic cells (FDC) "star fish", and the professional dendretic cells. • Explain the light and dark zone. • Explain the importance of, lymph node, high endothelial venules, spleen, thymus, bone marrow, and Peyer's patches. • Define the M cells. • Explain the systemic lymphoid system, such as: A. Spleen B. Lymph node C. Mucosal system includes all the lymphoid tissues associated with mucosal surfaces. • Explain the importance of the presence of the phagocytic cells in the peripheral (secondary) lymphoid tissues. • Define the lymphocytes circulation within the mucosal lymphoid system. • Define the mucosal associated lymphoid tissues (MALT). • Define the mucosal lymphocytes, such as those found in the connective tissues and are called Lamina propria lymphocytes (LPLs), and Intra- epithelial lymphocytes (IELs). LECTURE REFRENCE: 1. TEXTBOOK: ROITT, BROSTOFF, MALE IMMUNOLOGY. 6th edition. Chapter 2. pp. 15-44 2. TEXTBOOK: ABUL K. ABBAS. ANDREW H. LICHTMAN. CELLULAR AND MOLECULAR IMMUNOLOGY. 5TH EDITION. Chapter 2. pg 26-39. 1 THE LYMPHOID SYSTEM Overview The lymphoid cell line traces its origin to a pluripotential stem cell that in the fetus is found within the yolk sac, bone marrow, and liver and in the adult in the bone marrow. The differentiation of the stem cell to lymphoid or myeloid pathways is dependent upon the microenvironments in which these stem cells develop. These environments are provided in what is called the lymphoid system.
    [Show full text]
  • Hevs, Lymphatics and Homeostatic Immune Cell Trafficking in Lymph Nodes
    REVIEWS HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes Jean-Philippe Girard1,2, Christine Moussion1,2,3* and Reinhold Förster4 Abstract | In search of foreign antigens, lymphocytes recirculate from the blood, through lymph nodes, into lymphatics and back to the blood. Dendritic cells also migrate to lymph nodes for optimal interaction with lymphocytes. This continuous trafficking of immune cells into and out of lymph nodes is essential for immune surveillance of foreign invaders. In this article, we review our current understanding of the functions of high endothelial venules (HEVs), stroma and lymphatics in the entry, positioning and exit of immune cells in lymph nodes during homeostasis, and we highlight the unexpected role of dendritic cells in the control of lymphocyte homing through HEVs. Lymph The trafficking of immune cells in lymph nodes has a of B and T cells (as well as DCs) are regulated by the Interstitial protein-poor aqueous crucial role in immunity. The hundreds of lymph nodes chemokine ligands CC-chemokine ligand 21 (CCL21), fluid in the extravascular space (~450) that are dispersed in the human body are essential CCL19 and CXC-chemokine ligand 13 (CXCL13) that that is channelled in lymphatic for the encounter of circulating naive lymphocytes with are produced by fibroblastic reticular cells (FRCs) in the vessels and returned to the follicular dendritic cells circulation via the thoracic duct. antigens and antigen-presenting cells, such as dendritic T cell areas and by (FDCs) in the cells (DCs), which drain from peripheral tissues through B cell follicles9–12. If lymphocytes do not recognize their interstitial fluids (lymph).
    [Show full text]