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Elucidating the mechanism and the functional significance of leukocyte migration through afferent lymphatic vessels

English title Elucidating the mechanism and the functional significance of leukocyte migration through afferent lymphatic vessels
Applicant Halin Cornelia
Number 156269
Funding scheme Project funding (Div. I-III)
Research institution Institut für Pharmazeutische Wissenschaften ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Immunology, Immunopathology
Start/End 01.01.2015 - 31.12.2017
Approved amount 565'436.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Cardiovascular Research

Keywords (4)

Leukocyte trafficking; immunity; lymphatic vessels; vascular biology

Lay Summary (German)

Lead
Afferente Lymphgefässe ermöglichen die Migration von dendritischen Zellen und anderen Leukozyten aus Geweben in die drainierenden Lymphknoten und spielen somit eine zentrale Rolle bei der Induktion von Immunantworten. Im Gegensatz zur Leukozytenmigration durch Blutgefässe wurde die Migration durch Lymphgefässe bisher kaum erforscht.
Lay summary

Inhalt und Ziele des Forschungsprojekts

Unsere auf Intravitalmikroskopie basierenden Forschungsergebnisse haben kürzlich gezeigt, dass dendritische Zellen in den Lymphkapillaren der Haut aktiv migrieren und erst in den tieferen Sammelgefässen passiv mit dem Lymphstrom transportiert werden. Interessanterweise beobachten wir, dass die Zellen in den Lymphkapillaren hin und her patrouillieren und oft für längere Zeit anhalten. Ziel dieses Projekts ist es, die molekularen Mechanismen und Relevanz der intralymphatischen Leukozytenmigration besser zu erforschen. Konkret werden wir untersuchen, welche molekularen Signale die Richtung der Leukozytenmigration in den Lymphkapillaren bestimmen. Des Weiteren werden wir eine Genexpressions-Analyse von Lymphgefäss-Zellen durchführen. Dafür werden wir Zellen aus den Lymphkapillaren und Sammelgefässen der Haut isolieren. Mittels dieser Studie werden wir Genexpressionsunterschiede in Kapillar- und Sammelgefässen identifizieren und versuchen, diese mit dem Migrationsverhalten der Leukozyten in den beiden Gefässabschnitten zu korrelieren. In einem dritten Teilprojekt werden wir erforschen, warum Leukozyten in den Lymphkapillaren anhalten. Insbesondere werden wir untersuchen, ob das Anhalten auf intralymphatische Interaktionen zwischen Leukozyten zurückzuführen sein könnte.

 

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Unser Projekt wird fundamentale neue Erkenntnisse über die Migration von Immunzellen durch Lymphgefässe liefern. Zudem werden unsere Resultate zeigen, ob Lymphgefässe  - ähnlich wie Lymphknoten – Strukturen sind, in denen Immunzellen interagieren und Immunantworten induziert sowie reguliert werden. Eine derartige Erkenntnis könnte das heutige Verständnis der Rolle von Lymphgefässen in der Immunantwort um einen wichtigen Aspekt erweitern.

Direct link to Lay Summary Last update: 02.10.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Microinjection for the ex Vivo Modification of Cells with Artificial Organelles
Tiefenboeck P, Kim JA, Trunk F, Eicher T, Russo E, Teijeira A, Halin C, Leroux JC (2017), Microinjection for the ex Vivo Modification of Cells with Artificial Organelles, in ACS Nano, 11(8), 7758-7769.
T Cell Migration from Inflamed Skin to Draining Lymph Nodes Requires Intralymphatic Crawling Supported by ICAM-1/LFA-1 Interactions
Teijeira M, Hunter M, Russo E, Proulx ST, Frei T, Debes G, Coles M, Melero I, Detmar M, Rouzaut A, Halin C (2017), T Cell Migration from Inflamed Skin to Draining Lymph Nodes Requires Intralymphatic Crawling Supported by ICAM-1/LFA-1 Interactions, in Cell Reports, 18(4), 857-865.
T Cell Trafficking through Lymphatic Vessels
Hunter M, Teijeira A, Halin C (2016), T Cell Trafficking through Lymphatic Vessels, in Front Immunol, 7, 613.
Intralymphatic CCL21 Promotes Tissue Egress of Dendritic Cells through Afferent Lymphatic Vessels
Russo E, Teijeira A, Vaahtomeri K, Willrodt AH, Bloch J, Nitschké M, Santambrogio L, Kerjaschki D, Sixt M, Halin C (2016), Intralymphatic CCL21 Promotes Tissue Egress of Dendritic Cells through Afferent Lymphatic Vessels, in Cell Reports, 14(7), 1723-1734.
Editorial: Breaching their way through: Neutrophils destroy intercellular junctions to transmigrate rapidly across lymphatic endothelium
Teijeira A., Halin C. (2015), Editorial: Breaching their way through: Neutrophils destroy intercellular junctions to transmigrate rapidly across lymphatic endothelium, in Journal of Leukocyte Biology, 98(6), 880-882.

Collaboration

Group / person Country
Types of collaboration
Dr. Mark Coles, University of York, UK Great Britain and Northern Ireland (Europe)
- Publication
- Research Infrastructure
Dr. Gudrun Debes, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Laura Santambrogio, Yeshiva University, New York, NY United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Friedemann Kiefer, Max-Planck-Institut für molekulare Biomedizin, Münster Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Santiago Gonzalez, Institute for Research in Biomedicine (IRB) in Bellinzona Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Michael Sixt, Institute of Science and Technology Austria (IST Austria) Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Alvaro Teijeira, Universidad Pública de Navarra, Pamplona Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Lecture, Universität Fribourg Individual talk Intravital imaging of leukocyte migration through afferent lymphatic vessels 15.11.2017 Fribourg, Switzerland Halin Cornelia;
FOR 2240 Symposium: Innovative conceps in anti-inflammatory therapies Talk given at a conference Intravital imaging of leukocyte migration through afferent lymphatic vessels 20.10.2017 Köln, Germany Halin Cornelia;
Cornell University, Medical Faculty Individual talk Leukocyte migration through afferent lymphatic vessels 09.08.2017 Ithaka, NY, United States of America Halin Cornelia;
ESM-EVBO Meeting Talk given at a conference Intravital imaging of leukocyte migration through afferent lymphatic vessels 01.06.2017 Genf, Switzerland Halin Cornelia;
National Cytomeet Meeting Talk given at a conference Leukocyte migration through afferent lymphatic vessels 24.01.2017 Bern, Switzerland Halin Cornelia;
17th Congress of the Union of the Swiss society of Vascular Diseases Poster Identification of new genes involved in leukocyte migration through afferent lymphatic vessels 05.10.2016 Bern, Switzerland Arasa Aparici Jorge;
International meeting on “Imaging the Immune System” II, Weizmann Institute of Science Talk given at a conference Leukocyte migration through afferent lymphatic vessels 19.06.2016 Rehovot, Israel Halin Cornelia;
International meeting on “Imaging the Immune System” II, Weizmann Institute of Science Poster T cells migration from inflamed skin to draining lymph nodes requires ICAM-1 and intralymphatic crawling 19.06.2016 Rehovot, Israel Hunter Morgan Campbell;
Vortrag, Medizinische Fakultät Universität Genf Individual talk Leukocyte migration through afferent lymphatic vessels 10.06.2016 Genf, Switzerland Halin Cornelia;
Gordon Research Conference: Lymphatics Poster CCL21 and ICAM1 expression along the afferent lymphatic vasculature 20.03.2016 Ventura, CA, United States of America Arasa Aparici Jorge;
Joint Cancer Meeting Talk given at a conference Investigating the vascular–immune crosstalk 16.11.2015 Zurich, Switzerland Halin Cornelia;
NIH Lymphatics Symposium Talk given at a conference Mechanisms of leukocyte trafficking into and in the lymphatic system 30.09.2015 Bethesda, United States of America Halin Cornelia;
10th World Congress for Microcirculation Talk given at a conference Dendritic cell migration through afferent lymphatic vessels 26.09.2015 Kyoto, Japan Halin Cornelia;
41st European Society of Lymphology (ESL) Congress Talk given at a conference Lymphatics and Cellular Trafficking 05.06.2015 Lausanne, Switzerland Halin Cornelia;
Lecture, University Hospital Zurich (Dermatology) Individual talk New insights into the immune and drainage functions of lymphatic vessels 01.04.2015 Zurich, Switzerland Halin Cornelia;
Lecture, University of Bergen Talk given at a conference New insights into the immune and drainage functions of lymphatic vessels 26.02.2015 Bergen, Norway Halin Cornelia;
Vascular Biology Meeting Talk given at a conference Lymphatic vessels in inflammation and immunity 23.01.2015 Vienna, Austria Halin Cornelia;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Zur richtigen Zeit am richtigen Ort: Wieso und wie Immunzellen in unserem Körper migrieren German-speaking Switzerland 2017
New media (web, blogs, podcasts, news feeds etc.) Signpost for sentinel cells ETH News International 2016

Associated projects

Number Title Start Funding scheme
116128 Identification of adhesion molecules involved in dendrtic cell migration into lymphatics 01.05.2007 Project funding (Div. I-III)
182528 Interactions of Leukocytes within and with Lymphatic Vessels: Elucidating their Impact on Immune Regulation and Leukocyte Migration 01.10.2018 Project funding (Div. I-III)

Abstract

Afferent lymphatic vessels (LVs) fulfill important immune functions by transporting soluble antigen and leukocytes, such as dendritic cells (DCs) or recirculating CD4+ T cells, to draining lymph nodes (dLNs). Especially the migration of DCs from peripheral tissues to dLNs is well-known to be essential for sustaining peripheral tolerance or for promoting immune responses against pathogens. Performing intravital microscopy (IVM) in the murine ear skin our group has recently reported that DCs actively crawl within afferent lymphatic capillaries and appear to only be passively drained by flow once they reach downstream collecting vessels. Interestingly, DC migration within LV capillaries resembled a vascular patrolling behavior; while some intralymphatic DCs remained immotile for long time periods, the majority migrated in a semi-directed fashion within lymphatic capillaries (i.e. taking frequent turns). The Overall Aim of this proposal is to further characterize the mechanism and functional significance of leukocyte migration and behavior within afferent LVs. For example, we plan to investigate the mechanisms that promote directed crawling of intralymphatic DCs in downstream direction of the dLN. Using IVM we have compiled preliminary evidence that CCL21 is involved in this process and hypothesize that an intralymphatic CCL21 gradient, deposited by the lymph flow, guides DCs in downstream direction. In Subproject A we therefore plan to determine whether CCL21 regulates the directionality of intralymphatic DC migration, as suggested by our preliminary data. This will be addressed by performing IVM or time-lapse imaging in skin explants, as well as in vitro flow chamber studies. Another sub-aim of this proposal is to investigate whether the patrolling / arresting behavior of DCs within lymphatic capillaries has a functional significance in the immune response. Given that the majority of leukocytes migrating through afferent LVs reportedly are CD4+ T cells, we hypothesize that DCs might be interacting with these cells and might already be fulfilling antigen-presenting functions within LVs. In Subproject B we therefore plan to determine whether intralymphatic DC-T cell interactions occur and to investigate the immunologic significance of such interactions. These aims will be addressed using various gene-targeted mouse strains, amongst them T cell receptor (TCR)-transgenic mice and fluorescent reporter mice, in combination with IVM or ex vivo analyses. Finally, in Subproject C, we plan to identify new genes involved in leukocyte migration within lymphatic vessels and to correlate gene expression in lymphatic capillaries and collectors with differences in the mode of leukocyte migration in these two vessel segments (i.e. crawling vs. flowing). To this end, we will perform a comprehensive gene expression analysis of lymphatic endothelial cells (LECs) isolated by FACS-sorting from dermal LV capillaries or collectors. Overall, our project will generate fundamental new insights into the process of leukocyte migration within LVs - a migratory step that has been much less well characterized as compared to leukocyte trafficking through blood vessels (BVs). In addition to establishing the molecular mechanism of this process, the project will investigate whether afferent LVs represent a compartment in which DCs and T cells interact and adaptive immune responses are induced or modulated. A confirmation of this concept would significantly change and extend the current perspective on the role that LVs play in the immune response.
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