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Anatomical routes and molecular mechanisms of T cell migration across the brain barriers

English title Anatomical routes and molecular mechanisms of T cell migration across the brain barriers
Applicant Engelhardt Britta
Number 170131
Funding scheme Project funding (Div. I-III)
Research institution Theodor Kocher Institut Medizinische Fakultät Universität Bern
Institution of higher education University of Berne - BE
Main discipline Immunology, Immunopathology
Start/End 01.10.2016 - 30.09.2019
Approved amount 600'000.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Neurophysiology and Brain Research

Keywords (8)

blood-cerebrospinal fluid barrier; adhesion molecules; CNS immunosurveillance; live cell imaging; experimental autoimmune encephalomyelitis; blood-brain barrier; T cell subsets (Th1, Th17, Tc1, Tc17); T cell trafficking

Lay Summary (German)

Lead
Wege und Mechanismen der T Zell Wanderung über die Gehirnschranken
Lay summary

Das zentrale Nervensystem (ZNS) ist ein immunprivilegiertes Organ. Der spezielle Aufbau des ZNS erlaubt eine Immunüberwachung ohne die elektrische Kommunikation der Nervenzellen zu stören. Der Aufbau des ZNS ähnelt einer Burg, die mit zwei Mauern umgeben ist. Die innere Mauer, hinter welcher die Nervenzellen kommunizieren, wird durch Gliazellen gebildet, die im gesunden Organismus den Zutritt des Immunsystems in das ZNS verhindert. Die äusseren Mauern werden von den Zellen der Blut-Hirn Schranke (BHS) und der Blut-Liquor Schranke (BLS) gebildet. Die BHS und BLS erlauben es erfahrenen Immunzellen (aktivierten CD4 und CD8 T Zellen), in den “Burggraben”, das ist der Liquor gefüllte Raum, der das ZNS Gewebe umgibt, einzuwandern und so die Immunüberwachung des ZNS zu gewährleisten.

In unserem Forschungsprojekt untersuchen wir die Rolle der BHS versus BLS in der Regulation der T Zellwanderung in das ZNS im gesunden Organismus und wollen herausfinden, wie sich die Rolle dieser beiden Barrieren bei entzündlichen Erkrankungen des ZNS, z.B. der Multiplen Sklerose oder dem Schlaganfall ändert. Ausserdem wollen wir herausfinden, welche T Zellpopulationen eher über die BHS oder BLS Zugang in das ZNS erhalten. Dabei beziehen wir in unsere Untersuchungen T Zellpopulationen mit ein, welche bislang wenig untersucht wurden.

Wir verwenden transgene Mausmodelle in Kombination mit modernen mikroskopische Techniken, da dies erlaubt, die T  Zellwanderung in in vitro und in vivo live zu beobachten.

Ziel des Projektes ist es, die molekularen Mechanismen, welche die T Zellwanderung in das ZNS über die BHS und BLS regulieren zu definieren und so neue therapeutische Zielstrukturen für die Behandlung entzündlicher Erkrankungen des ZNS zu definieren.

Direct link to Lay Summary Last update: 26.09.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
PECAM-1 Stabilizes Blood-Brain Barrier Integrity and Favors Paracellular T-Cell Diapedesis Across the Blood-Brain Barrier During Neuroinflammation
Wimmer Isabella, Tietz Silvia, Nishihara Hideaki, Deutsch Urban, Sallusto Federica, Gosselet Fabien, Lyck Ruth, Muller William A., Lassmann Hans, Engelhardt Britta (2019), PECAM-1 Stabilizes Blood-Brain Barrier Integrity and Favors Paracellular T-Cell Diapedesis Across the Blood-Brain Barrier During Neuroinflammation, in Frontiers in Immunology, 10, 711.
Lack of junctional adhesion molecule (JAM)-B ameliorates experimental autoimmune encephalomyelitis
Tietz Silvia, Périnat Therese, Greene Gretchen, Enzmann Gaby, Deutsch Urban, Adams Ralf, Imhof Beat, Aurrand-Lions Michel, Engelhardt Britta (2018), Lack of junctional adhesion molecule (JAM)-B ameliorates experimental autoimmune encephalomyelitis, in Brain, Behavior, and Immunity, 73, 3-20.

Collaboration

Group / person Country
Types of collaboration
Prof. Thomas Hünig Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Thorsten Mempel United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Ronen Alon Israel (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Benoit Zuber Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Doron Merkler Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Associated projects

Number Title Start Funding scheme
137127 ProDoc Cell Migration Research Module I: Immune cell migration in immunosurveillance and inflammation 01.10.2011 ProDoc
189080 Brain Barriers ID: Identifying and detailing the molecular mechanisms regulating integrity and immune function of the brain barriers 01.10.2019 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)
154483 Unraveling the immune etiology of multiple sclerosis - UnmetMS 01.10.2014 Sinergia
137127 ProDoc Cell Migration Research Module I: Immune cell migration in immunosurveillance and inflammation 01.10.2011 ProDoc
183501 Installing a Hyperion CyTOF mass cytometry platform for high-dimensional single cell analysis at the University of Bern 01.10.2019 R'EQUIP

Abstract

The endothelial blood-brain barrier (BBB) in central nervous system (CNS) microvessels and the epithelial blood-cerebrospinal fluid barrier (BCSFB) in the choroid plexus establish the interface between the immune system and the CNS. Several aspects of their function to maintain CNS homeostasis contribute to rigorous control of immune cell trafficking into the CNS. Passage into the CNS is therefore limited to immune cell subsets that hold molecular keys required to breach these barriers. During homeostatic CNS immunosurveillance specific T cell subsets breach the brain barriers but remain confined to the cerebrospinal fluid (CSF) filled ventricular and leptomeningeal spaces. In contrast, in multiple sclerosis (MS) or in its animal model, experimental autoimmune encephalomyelitis (EAE), barrier properties of the BBB and BCSFB change and allow the migration of pathogenic T cells into the CNS. Therapeutic targeting of T cell migration into the CNS has proven beneficial for the treatment of MS but in rare cases it is associated with severe side effects like progressive multifocal leukoencephalopathy (PML). This has raised significant concerns about the safety of therapies targeting T cell trafficking as these might also affect the migration of beneficial T cell subsets maintaining immunosurveillance of the CNS. However, the anatomical routes and molecular mechanisms involved in T cell migration into the CNS during immunosurveillance and how these mechanisms differ in brain and psinal cord and change during neuroinflammation are not sufficiently explored. Our previous research has significantly contributed to the notion that different T cell subsets like effector CD4+ Th1 versus Th17 cells or CD8+ T cells use different anatomical routes and different molecular mechanisms to breach the brain barriers during onset and progression of CNS neuroinflammation. Furthermore, we have shown an active contribution of the BBB which depending on its inflammatory status directs T cells to paracellular or transcellular sites of diapedesis. The proposed research project aims to uncover the anatomical routes and molecular cues used by different CD4 and CD8 effector T cell subsets for breaching the BBB or the BCSFB during immunosurveillance and neuroinflammation. To address this challenging task we have combined a unique armamentarium of in vivo models of Th1, Th17 and CD8 T cell mediated autoimmune CNS inflammation combined with in vitro models of the BBB and the BCSFB and in vitro and in vivo live cell imaging technology to study T cell interaction with the brain barriers. Under Specific Aim 1 we will dissect the role of cell adhesion molecules from the Ig superfamily (IgCAMs) in Th1 versus Th17 migration across the brain barriers during immunosurveillance and EAE and the role for paracellular versus transcellular diapedesis pathways of T cells across the BBB and the mechanisms involved. Specific Aim 2 is dedicated to explore the molecular mechanism involved in CD8 T cell migration into the CNS during immunosurveillance and neuroinflammation employing a mouse model of CD8 T cell mediated autoimmune CNS inflammation. Finally, to explore the relevance of the BBB versus the BCSFB as T cell entry port into the CNS we will investigate under Specific Aim 3 the role of the choroid plexus as alternative entry site of T cells into the CSF space during immunosurveillance and neuroinflammation. Exploring these research goals in parallel is prerequisite for obtaining the unique opportunity for direct cross-fertilization of the respective projects and thus increasing awareness for differences observed for the different T cell subsets in crossing the brain barriers. Our research will serve to significantly improve our understanding of the anatomical routes and molecular mechanisms guiding different T cell subsets into the CNS during immunosurveillance and neuroinflammation. In general, this will set the stage to more accurately foresee CNS specific adverse effects of the increasing numbers of therapies targeting T cell trafficking or even depleting T cells in many chronic inflammatory diseases. Additionally, this will allow to identify novel therapeutic targets at the level of the brain barriers suited to specifically block CNS recruitment of destructive T cells, while leaving the migration of protective T cell subsets into the CNS unaffected.
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