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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.

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Last update: 21.02.2013

Active participation

Communication	Title	Media	Place	Year

Number	Title	Start	Funding scheme

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.