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Molecular mechanisms guiding lymphocyte development

English title Molecular mechanisms guiding lymphocyte development
Applicant De Libero Gennaro
Number 160330
Funding scheme Project funding (Div. I-III)
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Immunology, Immunopathology
Start/End 01.04.2015 - 31.01.2019
Approved amount 756'000.00
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Keywords (4)

Duxbl; hematopoietic stem cells; cytokines and hematopietic development; IL-2 anti IL-2 immunecomplexes

Lay Summary (German)

Lead
Molecular mechanisms guiding lymphocyte development
Lay summary

Die Entwicklung des adaptiven Immunsystems ist ein hoch dynamischer und komplexer Prozess. Die molekularen Mechanismen, welche diesen lenken, sind bisher nicht vollkommen verstanden. Das Hauptanliegen der in diesem Antrag beschriebenen Projekte ist die molekularen und zellulären Mechanismen, welche die normale Entwicklung von Lymphozyten bewirken, besser zu verstehen. Verschiedene humane Krankheiten, wie zum Beispiel Leukämien und Lymphome, Autoimmunerkrankungen und Immundefizienzsyndrome, werden teilweise durch Abnormalitäten in diesem Entwicklungsprozess ausgelöst. Daher würde ein besseres Verständnis der normalen Entwicklung von Lymphozyten helfen die molekularen Mechanismen dieser Krankheiten aufzuklären.

In unseren Projekten legen wir speziellen Wert auf das Zusammenspiel von IL-7 und FLT3L, zwei Zytokine die eine wichtige Rolle für die frühe hämatopoietische Entwicklung spielen. Daher werden Mäuse, die für diese Zytokine defizient sind und/oder diese überexprimieren, generiert und im Detail analysiert. Außerdem werden wir versuchen die Rolle des Transkriptionsfaktors Duxbl in der hämatopoietischen Entwicklung zu verstehen. Erste Experimente haben gezeigt, dass die Überexpression von Duxbl im hämatopoietischen System einen Unterbruch der T-Zell Entwicklung im Thymus und der B-Zell Entwicklung im Knochenmark auslöst. Diese Ergebnisse lassen vermuten, dass dieser Transkriptionsfaktor eine entscheidende Rolle in der frühen Lymphozytenentwicklung spielt, welche vorher noch nicht wahrgenommen wurde.

Direct link to Lay Summary Last update: 07.05.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
The transcription factor Duxbl mediates elimination of pre-T cells that fail β-selection
Klein Fabian, Mitrovic Mladen, Roux Julien, Engdahl Corinne, von Muenchow Lilly, Alberti-Servera Llucia, Fehling Hans Jörg, Pelczar Pawel, Rolink Antonius, Tsapogas Panagiotis (2019), The transcription factor Duxbl mediates elimination of pre-T cells that fail β-selection, in The Journal of Experimental Medicine, 216(3), 638-655.
Testosterone is an endogenous regulator of BAFF and splenic B cell number
Wilhelmson Anna S., Lantero Rodriguez Marta, Stubelius Alexandra, Fogelstrand Per, Johansson Inger, Buechler Matthew B., Lianoglou Steve, Kapoor Varun N., Johansson Maria E., Fagman Johan B., Duhlin Amanda, Tripathi Prabhanshu, Camponeschi Alessandro, Porse Bo T., Rolink Antonius G., Nissbrandt Hans, Turley Shannon J., Carlsten Hans, Mårtensson Inga-Lill, Karlsson Mikael C. I., Tivesten Åsa (2018), Testosterone is an endogenous regulator of BAFF and splenic B cell number, in Nature Communications, 9(1), 2067-2067.
A loop region of BAFF controls B cell survival and regulates recognition by different inhibitors
Vigolo Michele, Chambers Melissa G., Willen Laure, Chevalley Dehlia, Maskos Klaus, Lammens Alfred, Tardivel Aubry, Das Dolon, Kowalczyk-Quintas Christine, Schuepbach-Mallepell Sonia, Smulski Cristian R., Eslami Mahya, Rolink Antonius, Hummler Edith, Samy Eileen, Fomekong Nanfack Yves, Mackay Fabienne, Liao Maofu, Hess Henry, Jiang Xuliang, Schneider Pascal (2018), A loop region of BAFF controls B cell survival and regulates recognition by different inhibitors, in Nature Communications, 9(1), 1199-1199.
Accumulation of Multipotent Hematopoietic Progenitors in Peripheral Lymphoid Organs of Mice Over-expressing Interleukin-7 and Flt3-Ligand
Klein Fabian, von Muenchow Lilly, Capoferri Giuseppina, Heiler Stefan, Alberti-Servera Llucia, Rolink Hannie, Engdahl Corinne, Rolink Michael, Mitrovic Mladen, Cvijetic Grozdan, Andersson Jan, Ceredig Rhodri, Tsapogas Panagiotis, Rolink Antonius (2018), Accumulation of Multipotent Hematopoietic Progenitors in Peripheral Lymphoid Organs of Mice Over-expressing Interleukin-7 and Flt3-Ligand, in Frontiers in Immunology, 9, 1.
DN2 Thymocytes Activate a Specific Robust DNA Damage Response to Ionizing Radiation-Induced DNA Double-Strand Breaks
Calvo-Asensio Irene, Sugrue Tara, Bosco Nabil, Rolink Antonius, Ceredig Rhodri (2018), DN2 Thymocytes Activate a Specific Robust DNA Damage Response to Ionizing Radiation-Induced DNA Double-Strand Breaks, in Frontiers in Immunology, 9, 1.
Prophylactic and Therapeutic Effects of Interleukin-2 (IL-2)/Anti-IL-2 Complexes in Systemic Lupus Erythematosus-Like Chronic Graft-Versus-Host Disease
Heiler Stefan, Lötscher Jonas, Kreuzaler Matthias, Rolink Johanna, Rolink Antonius (2018), Prophylactic and Therapeutic Effects of Interleukin-2 (IL-2)/Anti-IL-2 Complexes in Systemic Lupus Erythematosus-Like Chronic Graft-Versus-Host Disease, in Frontiers in Immunology, 9, 1.
Two Distinct Pathways in Mice Generate Antinuclear Antigen-Reactive B Cell Repertoires
Faderl Martin, Klein Fabian, Wirz Oliver F., Heiler Stefan, Albertí-Servera Llucia, Engdahl Corinne, Andersson Jan, Rolink Antonius (2018), Two Distinct Pathways in Mice Generate Antinuclear Antigen-Reactive B Cell Repertoires, in Frontiers in Immunology, 9, 1.
De novo Classification of Mouse B Cell Types using Surfaceome Proteotype Maps
(2018), De novo Classification of Mouse B Cell Types using Surfaceome Proteotype Maps, in De novo Classification of Mouse B Cell Types using Surfaceome Proteotype Maps, 1.

Associated projects

Number Title Start Funding scheme
140672 Molecular mechanisms guiding lymphocyte development 01.04.2012 Project funding (Div. I-III)

Abstract

In the next period we will continue the projects that we already initiated in the passed period. These projects include:1.Nup98/HoxB4 immortalized hematopoietic stem cells.These cells will used to analyze the function of the differentially expressed genes in the 4 EPLM subpopulations. Moreover, we will establish the CRISPR/Cas9 genetic editing system in these HSC’s.2.The transcription factor DuxblWe will decipher the molecular mechanism underlying the apoptosis induction by Duxbl. Moreover, we will analyze the effect of Duxbl silencing on B and T cell development. Especially we will test if this silencing can improve T cell development in preTa deficient mice and B cell development in ?5 deficient mice.3.The interplay of FLT3L and IL-7 in early hematopoietic development.We will perform RNA sequencing on the 4 EPLM subpopulations in order to identify differentially expressed genes. The function of these genes will be tested in the immortalized HSC’s (see above). Moreover, we will analyze the interplay of FLT3L and IL-7 in the development of the EPLM populations. Therefore, wild type, FLT3L transgenic, IL-7 transgenic, FLT3l deficient, IL-7 deficient, FLT3l deficient IL-7 transgenic, IL-7 deficient FLT3L transgenic and FLT3L and IL-7 double transgenic mice will be generated and analyzed. 4.The potential of IL-2 anti IL-2 immune complexes in preventing and/or inhibiting chronic Graft versus Host Disease (GVHD)The chronic Graft versus Host reaction results in the development of a disease resembling systemic lupus erythematosus in man. Now we will analyze if IL-2 anti IL-2 immune complexes which can expand various T cell subsets can prevent and/or inhibit this disease development.
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