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ProDoc Cell Migration Research Module I: Immune cell migration in immunosurveillance and inflammation

English title ProDoc Cell Migration Research Module I: Immune cell migration in immunosurveillance and inflammation
Applicant Engelhardt Britta
Number 137127
Funding scheme ProDoc
Research institution Theodor Kocher Institut Medizinische Fakultät Universität Bern
Institution of higher education University of Berne - BE
Main discipline Immunology, Immunopathology
Start/End 01.10.2011 - 31.01.2016
Approved amount 613'365.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Neurophysiology and Brain Research

Lay Summary (German)

Lead
Lay summary
Das Forschungsmodul 1 "Immunzellwanderung bei der Immunüberwachung und Entzündung" ist Teil des Ausbildungsprogrammes Pro Doc "Cell Migration" für Doktorierende. Das Program wird gemeinsam von Wissenschaflern des Theodor Kocher Institutes der Universität Bern, von der Universität Freiburg und vom Institut für Biomedizinische Forschung, Bellinzona durchgeführt. Das Program besteht darüber hinaus aus einem zweiten Forschungmodul "Zellmigration bei der Tumormetastasierung" und einem Ausbidlungsmodul. Im Rahmen des Forschungsmodules 1 promovieren 8 Doktoriernde auf verschiedenen Themen der Immunzellwanderung. Die Themen erstrecken sich von Untersuchungen zur Wanderung von bestimmten Immunzellpopulationen in die Lymphknoten bis hin zur Analyse detaillierter molekularer Mechanismen der Immunzellwanderung in entzündete Organe.  Die Doktorarbeiten werden jeweils in Zusammenarbeit der beteiligten Institutionen durchgeführt, so dass die Doktoranden ihre praktischen Arbeiten an verschiedenen Institutionen durchführen und so optimal von den sich ergänzenden Expertisen, welche die Partnerinstitutionen in das ProDoc "Cell Migration" einfliessen lassen, profitieren.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Modeling immune functions of the mouse blood-cerebrospinal fluid barrier in vitro: primary rather than immortalized mouse choroid plexus epithelial cells are suited to study immune cell migration acro
Lazarevic Ivana, Engelhardt Britta (2016), Modeling immune functions of the mouse blood-cerebrospinal fluid barrier in vitro: primary rather than immortalized mouse choroid plexus epithelial cells are suited to study immune cell migration acro, in Fluids Barriers of CNS, 13(2), 1.

Collaboration

Group / person Country
Types of collaboration
Dr. Alexander Rudensky, Memorial Sloan-Kettering Cancer Center United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Joshua Weiner, Iowa United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Scott Barnum United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Michael Hertl, University of Marburg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
FP 7 European Stroke Network Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Dietmar Vestweber Germany (Europe)
- Publication
Prof. Antonio Uccelli, University of Genova Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
FP 7 JUSTBRAIN Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
1st Immunology Summer School Poster Migration, cell fate and the relationship of the follicular T helper cells with other T cell subsets in mice 05.05.2014 Bellinzona, Switzerland Wypych Tomasz;
WIRM Poster Mouse models of the blood cerebrospinal fluid barrier to study T cell trafficking into the CNS 19.03.2014 Davos, Switzerland Lazarevic Ivana; Engelhardt Britta;
GCB symposium Poster Mouse models of the blood cerebrospinal fluid barrier to study T cell trafficking into the CNS 29.01.2014 Bern, Switzerland Lazarevic Ivana; Engelhardt Britta;
GCB Symposium Poster Migration, cell fate and the relationship of the follicular T helper cells with other T cell subsets in mice 29.01.2014 Bern, Switzerland Sallusto Federica; Wypych Tomasz;
15th International Congress of Immunology in Milan Poster The role of B cells as antigen presenting cells in allergic inflammation 22.08.2013 Milan, Italy Wypych Tomasz;
10th International Conference on Cerebral Vascular Biology Poster Mouse models to study T cell trafficking across the BCSFB 18.06.2013 Montréal, Canada Lazarevic Ivana; Engelhardt Britta;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Das Virus und der verlorene Schuh German-speaking Switzerland 2014

Associated projects

Number Title Start Funding scheme
149475 Studies on T cell activation, differentiation and plasticity in humans 01.10.2013 Project funding (Div. I-III)
160439 The role of g-protocadherins in neuroinflammation 01.02.2015 International short research visits
170131 Anatomical routes and molecular mechanisms of T cell migration across the brain barriers 01.10.2016 Project funding (Div. I-III)
149420 Identification of trafficking molecules involved in the migration of CD8 T cells across the blood-brain barrier during immunosurveillance and neuroinflammation 01.10.2013 Project funding (Div. I-III)
125447 Examining the function of lymphoid organ structure during antiviral immune responses using microscopic and mesoscopic imaging 01.06.2009 Sinergia
141773 ProDoc Cell Migration Research Module 3: Soluble factors in Cell Migration 01.10.2012 ProDoc
133092 Defining the specific role of endothelial-expressed Ig-superfamily cell adhesion molecules (IgCAMs) in mediating the individual steps involved in T cell extravasation across the blood-brain barrier in vitro and in vivo 01.10.2010 Project funding (Div. I-III)
131092 Effector and memory T cell subsets in man and mouse 01.07.2010 Project funding (Div. I-III)
170131 Anatomical routes and molecular mechanisms of T cell migration across the brain barriers 01.10.2016 Project funding (Div. I-III)

Abstract

Specific immune responses require the timely interaction of various cell types within specific microenviron-ments. In primary responses rare specific naive T cells maximize the possibility of encounter with antigen-presenting dendritic cells (DCs) by recirculating through secondary lymphoid organs. In order to help B cells to produce high affinity antibodies, antigen-primed T follicular helper cells (TFH) migrate to the B cell follicles, where they induce germinal center (GC) reaction, while effector T cells exit lymphoid organs and migrate into the injured tissues. Memory T cells, that persist once antigen is eliminated, continually patrol their various tissue domains in search of evidence of re-attack. The different recirculation pathways of naïve, effector, and memory lymphocytes are established by unique molecular traffic signals - adhesion molecules, chemokines and their receptors - displayed on the immune cells and the respective tissue cells. Studies on the regulation and function of homing receptors in T lymphocytes and on how these receptors orchestrate cell positioning and interactions with other immune cells in secondary lymphoid tissues are central to our understanding of immune responses. Three PhD projects are dedicated to address specific questions in this area. As the generation of TFH cells remains unknown to date, ProDoc Student 1 will investigate generation and behaviour of CXCR5+ CD4+ TFH cells, as well as their relationship to other T helper cell subsets, in a novel transgenic mouse model allowing for lineage tracing in vivo. These studies will be complemented by the work of ProDoc Student 7 who will track circulating TFH cells in humans over a vaccine time course. ProDoc Student 8 will study the dynamics of T cell/DC interactions within the lymph node by performing an in depth analysis of the phenotype of migration defective DOCK2-/- and PI3K?-/- CD4+ T cells. Studying parenchymal motility of T cells and their interaction with DCs as a function of different peptide-MHC concentrations by means of two-photon-intravital microscopy (2P-IVM) of popliteal lymph node, will allow an integrated understanding of the molecular controls regulating T cell migration, their interaction with DCs and their activation. The further PhD projects within this RM are dedicated to study immune cell migration into peripheral organs with a strong focus on the central nervous system (CNS) in the context of immunosurveillance and inflammation. Based on our observation that activated Th17 cells cross the epithelial blood-cerebrospinal fluid barrier (BCSFB) at the level of the choroid plexus in a CCR6/CCL20 dependent way and cause experimental autoimmune encephalomyelitis (EAE), ProDoc Student 2 will investigate the cellular and molecular cues guiding T cell subsets across the BCSFB. By performing in depth expression studies as well as functional T cell/ BCSFB in vitro interaction assays, this thesis will highlight the relevance of the BCSFB as CNS entry site for T cell subsets during immunosurveillance and CNS inflammation. The further thesis projects are dedicated to study the molecular mechanisms involved in the multistep T cell interaction with the inflamed blood-brain barrier (BBB) during EAE. Specifically ProDoc Student 9 will investigate a4-integrin independent mechanisms of T cell rolling and capturing on the inflamed BBB in vivo by means of IVM and use of novel PSGL-1/E/P-selectin-/- SJL mouse models. ProDoc Students 10 and 11 will focus on the role of different immunoglobulin cell adhesion molecules (IgCAMs) in mediating post-arrest T cell interaction with the BBB in vitro and in vivo using live cell imaging and 2P-IVM combined with EAE studies, respectively. As an important extension of the work in the EAE model ProDoc Student 6 will perform a detailed analysis of the phenotype, function and chemokine receptor expression in autoreactive T cells in MS patients, which will provide important information as to the class and trafficking properties of human pathogenic T cells.
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