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Interactions of Leukocytes within and with Lymphatic Vessels: Elucidating their Impact on Immune Regulation and Leukocyte Migration

English title Interactions of Leukocytes within and with Lymphatic Vessels: Elucidating their Impact on Immune Regulation and Leukocyte Migration
Applicant Halin Cornelia
Number 182528
Funding scheme Project funding (Div. I-III)
Research institution Institut für Pharmazeutische Wissenschaften ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Cardiovascular Research
Start/End 01.10.2018 - 30.09.2022
Approved amount 700'000.00
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All Disciplines (2)

Discipline
Cardiovascular Research
Physiology : other topics

Keywords (9)

Vascular biology; Migration; Lymphatic vessels; Leukocyte trafficking; Immune function; Immunology; Dendritic cells; T cells; Regulatory T cells

Lay Summary (German)

Lead
Afferente Lymphgefässe ermöglichen die Migration von dendritischen Zellen und T Zellen aus Geweben in die drainierenden Lymphknoten und sind wichtig für die Induktion von Immunantworten. Wir haben kürzlich gezeigt, dass Leukozyten in den Lymphkapillaren der Haut aktiv migrieren. Erst wenn sie die tiefer gelegenen, kontrahierenden Lymphkollektor-Gefässe erreicht haben, lösen sie sich von der Gefässwand ab und werden passiv mit dem Lymphstrom zum Lymphknoten transportiert. Interessanterweise beobachten wir, dass Leukozyten viele Stunden in den Lymphkapillaren verweilen, wo sie einerseits mit den Lymphgefässzellen und andererseits miteinander interagieren. Diese Beobachtung lässt uns vermuten, dass Lymphkapillaren nicht nur Transportgefässe sind, sondern auch ein Ort, an dem Immunzellen und Immunantworten reguliert werden.
Lay summary

Inhalt und Ziele des Forschungsprojekts

Ziel dieses Projekts ist es, intralymphatische Zell-Interaktionen genauer zu charakterisieren. Insbesondere möchten wir die Wichtigkeit solcher Interaktionen in der Zellmigration und für die Immunfunktion untersuchen. Im ersten Teilprojekt beabsichtigen wir, mittels Intravitalmikroskopie und anderen zellbiologisch / molekularbiologischen Methoden die Bedeutung von  intralymphatischen Interaktionen zwischen dendritischen Zellen und T Zellen weiter zu erforschen. Im zweiten Teilprojekt werden wir untersuchen, ob zwei spezifische, in den Lymphgefässen exprimierte  immunmodulatorische Adhäsionsmoleküle die Migration und den Immunphänotyp von aus der Haut auswandernden T Zellen beeinflussen. Im dritten Teilprojekt werden wir ein neues, kürzlich von uns entdecktes Leukozyten-Migrationsmuster genauer und funktional untersuchen; nämlich die direkte Einwanderung von Leukozyten in die tiefer gelegenen Lymphkollektor-Gefässe.

 

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

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

 

Direct link to Lay Summary Last update: 04.10.2018

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
156269 Elucidating the mechanism and the functional significance of leukocyte migration through afferent lymphatic vessels 01.01.2015 Project funding (Div. I-III)

Abstract

Afferent lymphatic vessels (LVs) have long been known to mediate the transport of antigen and leukocytes to draining lymph nodes (dLNs), thereby serving as immunologic communication highways between peripheral tissues and LNs. The main cell types migrating via this route are antigen-presenting dendritic cells (DCs) and antigen-experienced T cells. While DC migration is important for maintenance of tolerance and for induction of protective immunity, T cell migration through afferent LVs contributes to immunesurveillance. Entry of leukocytes into afferent LVs is thought to primarily occur through specialized junctions present in initial lymphatic capillaries. Performing intravital microscopy (IVM) in the murine ear skin we have recently found and described that upon entry into capillaries, both DCs and T cells are not simply flushed away with the lymph flow, but actively crawl and patrol within the capillaries. Detachment and passive transport to the dLN only takes place once the cells have reached the downstream, contracting collecting vessel segments. Intriguingly, we have recently discovered that DCs and T cells within capillaries not only crawl, but also cluster and arrest in this compartment for hours, and even engage in intralymphatic DC-T cell interactions (unpublished observations). This peculiar behavior suggests that, besides propagating cells to dLNs, migration and cellular interactions within and with lymphatic capillaries might serve an additional biological purpose. The overall Aim of this proposal is to further characterize DC-T cell interactions occurring within LVs, as well as interactions between migrating leukocytes and lymphatic endothelial cells (LECs), and to study their impact on leukocyte trafficking and on immune function. In Subproject 1, we will perform IVM and trafficking studies to further investigate the occurrence and functional significance of cognate intralymphatic DC-T cell interactions. Given that we recently identified regulatory T cells (Tregs) as a major intralymphatic interaction partner of DCs, a particular focus will lie in investigating the relevance of intralymphatic DC-Treg interactions. Our hypothesis is that these interactions will impact the maturation phenotype of migrating DCs. In Subproject 2, on the other hand, we plan to investigate the role of CD112 and CD155, i.e. two adhesion molecules with immune-modulatory properties on T cells, which we recently found to be expressed in afferent LVs, in modulating the trafficking and immune phenotype of T cells emigrating from skin. This Subproject will rely on the use of various gene-targeted mouse models, such as (conditional) knock-outs and photo-convertible mice to assess the contribution of LEC-expressed CD112 and CD155 on migration and phenotype/function of skin-exiting T cells in dLNs. Finally, in Subproject 3 we plan to further investigate the occurrence and functional significance of DC entry into afferent lymphatic collectors - a process we recently found to contribute to enhancing DC migration in the context of tissue inflammation. Overall, our project will generate fundamental new insights into leukocyte migration through afferent LVs. In contrast to leukocyte trafficking through blood vessels (BVs), this process has been much less investigated so far. Most importantly, the project has the potential to identify afferent LVs as a new immune compartment in which adaptive immune responses are regulated. A confirmation of this novel concept would significantly change and extend the current perspective on the role of afferent LVs in the immune response.
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