Interferon regulatory factors 1 and 4 in T cell mediated immune modulation

The transcription factor interferon regulatory factor (IRF) 1 is essential for T helper cell 1 differentiation. Hereby, the respective Irf1 knockout mouse displays a severe immune defect and has an Th2 directed immune status per se. This effect is measurable by increased production of interleukin-4,...

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1. Verfasser: Mahiny, Azita Josefine
Beteiligte: Lohoff, Michael (Prof. Dr.) (BetreuerIn (Doktorarbeit))
Format: Dissertation
Sprache:Englisch
Veröffentlicht: Philipps-Universität Marburg 2011
Hygiene u. Med. Mikrobiologie mit Medizinaluntersuchungsamt
Ausgabe:http://dx.doi.org/10.17192/z2011.0561
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ref_str_mv references
topic IRF1
T Zellen
T Zellen
Knockout-Maus
knockout mouse
IRF4
IRF1
T cells
Cre-lox
IRF4
Cre-lox
Knockout-Maus
Cre-lox
Biowissenschaften, Biologie
IRF4
spellingShingle IRF1
T Zellen
T Zellen
Knockout-Maus
knockout mouse
IRF4
IRF1
T cells
Cre-lox
IRF4
Cre-lox
Knockout-Maus
Cre-lox
Biowissenschaften, Biologie
IRF4
Der Transkriptionsfaktor inteferon regulatory factor (IRF) 1 ist essentiell für die T Helfer (Th)-Zell-Differenzierung in Richtung Th1. Die entsprechende Knockout-Maus hat diesbezüglich einen so schwerwiegenden Defekt, daß sie per se eine Th2 gerichtete Immunantwort zeigt. Diese zeigt sich in einem erhöhten Level am Th2-Zytokin Interleukin (IL)-4 und einem erhöhten Immunglobulin E-Spiegel. Damit einhergehend ist diese Maus auch anfällig für intrazelluläre Pathogene, denen sie gegebenenfalls erliegt (z.B. eine Leishmania major-Infektion). Allergien zeigen ebenfalls eine Th2-gerichtete Immunantwort, daher lag die Vermutung nahe, daß die IRF1-defiziente Maus einen schweren Allergieverlauf aufweisen könnte. Im akuten murinen Asthmamodell, bei dem eine allergische Reaktion mittels Ovalbumin (OVA) provoziert wird, sollte diese Frage untersucht werden. Trotz breitgefächerter Analysen konnte in dieser Arbeit gezeigt werden, daß die IRF1 Maus erstaunlicherweise keine stärkere Pathologie entwickelt. Dieses Ergebnis macht besonders deutlich, daß die seit langem vorherrschende Meinung, daß Allergien, insbesondere Asthma, eine Th2-vermittelte Erkrankung sind, neu überdacht werden muß. Zur Zeit werden immer neue T helfer Subtypen beschrieben, die die hier gezeigten Ergebnisse weiter untermauern. Die IRF1 defiziente Maus weist auch einen Entwicklungsdefekt von CD8+ T Zellen auf, der deutlich macht, daß IRF1 auch andere Funktionen hat, die sich unabhängig von der T Helfer Zell-Differenzierung abspielen. In der Peripherie sind erheblich weniger CD8 positive Zellen zu finden, hauptsächlich weil im Thymus die MHCI-Präsentation fehlgeleitet ist. Um zellspezifische Funktionen von IRF1 aufzuklären, wurde im Rahmen dieser Arbeit eine für IRF1 konditionell getargetete Maus generiert, die sicherlich im Rahmen vielfältigster Fragestellungen hilfreich sein wird. Neben IRF1 hat IRF4 eine äquivalente Funktion in der Th2 Zelldifferenzierung, zusätzlich ist es aber ebenso wichtig für Th9 und Th17 Immunantworten. Im Fall der Th17 Zellen ist dieser Effekt derart drastisch, daß in der Irf4 Knockoutmaus keine Th17-Differenzierung stattfindet und die Maus im murinen Modell für Multiple Sklerose, der experimentellen autoimmunen Enzephalomylitis, für diese Krankheit vollständig resistent ist. Daher überraschte die in dieser Arbeit gezeigte IL-17 Produktion von IRF4 defizienten γδ T-Zellen. Obwohl der zugrundeliegende Mechanismus noch nicht aufgedeckt werden werden konnte, ist es dennoch möglich gewesen, im Rahmen dieser Arbeit verschiedene, naheliegende Signalwege auszuschließen und damit die Möglichkeiten stark einzugrenzen.
Mahiny, Azita Josefine
Interferon regulatory factors 1 and 4 in T cell mediated immune modulation
first_indexed 2011-09-06T00:00:00Z
contents Der Transkriptionsfaktor inteferon regulatory factor (IRF) 1 ist essentiell für die T Helfer (Th)-Zell-Differenzierung in Richtung Th1. Die entsprechende Knockout-Maus hat diesbezüglich einen so schwerwiegenden Defekt, daß sie per se eine Th2 gerichtete Immunantwort zeigt. Diese zeigt sich in einem erhöhten Level am Th2-Zytokin Interleukin (IL)-4 und einem erhöhten Immunglobulin E-Spiegel. Damit einhergehend ist diese Maus auch anfällig für intrazelluläre Pathogene, denen sie gegebenenfalls erliegt (z.B. eine Leishmania major-Infektion). Allergien zeigen ebenfalls eine Th2-gerichtete Immunantwort, daher lag die Vermutung nahe, daß die IRF1-defiziente Maus einen schweren Allergieverlauf aufweisen könnte. Im akuten murinen Asthmamodell, bei dem eine allergische Reaktion mittels Ovalbumin (OVA) provoziert wird, sollte diese Frage untersucht werden. Trotz breitgefächerter Analysen konnte in dieser Arbeit gezeigt werden, daß die IRF1 Maus erstaunlicherweise keine stärkere Pathologie entwickelt. Dieses Ergebnis macht besonders deutlich, daß die seit langem vorherrschende Meinung, daß Allergien, insbesondere Asthma, eine Th2-vermittelte Erkrankung sind, neu überdacht werden muß. Zur Zeit werden immer neue T helfer Subtypen beschrieben, die die hier gezeigten Ergebnisse weiter untermauern. Die IRF1 defiziente Maus weist auch einen Entwicklungsdefekt von CD8+ T Zellen auf, der deutlich macht, daß IRF1 auch andere Funktionen hat, die sich unabhängig von der T Helfer Zell-Differenzierung abspielen. In der Peripherie sind erheblich weniger CD8 positive Zellen zu finden, hauptsächlich weil im Thymus die MHCI-Präsentation fehlgeleitet ist. Um zellspezifische Funktionen von IRF1 aufzuklären, wurde im Rahmen dieser Arbeit eine für IRF1 konditionell getargetete Maus generiert, die sicherlich im Rahmen vielfältigster Fragestellungen hilfreich sein wird. Neben IRF1 hat IRF4 eine äquivalente Funktion in der Th2 Zelldifferenzierung, zusätzlich ist es aber ebenso wichtig für Th9 und Th17 Immunantworten. Im Fall der Th17 Zellen ist dieser Effekt derart drastisch, daß in der Irf4 Knockoutmaus keine Th17-Differenzierung stattfindet und die Maus im murinen Modell für Multiple Sklerose, der experimentellen autoimmunen Enzephalomylitis, für diese Krankheit vollständig resistent ist. Daher überraschte die in dieser Arbeit gezeigte IL-17 Produktion von IRF4 defizienten γδ T-Zellen. Obwohl der zugrundeliegende Mechanismus noch nicht aufgedeckt werden werden konnte, ist es dennoch möglich gewesen, im Rahmen dieser Arbeit verschiedene, naheliegende Signalwege auszuschließen und damit die Möglichkeiten stark einzugrenzen.
language English
license_str http://archiv.ub.uni-marburg.de/adm/urhg.html
oai_set_str_mv open_access
ddc:570
doc-type:doctoralThesis
xMetaDissPlus
doi_str_mv http://dx.doi.org/10.17192/z2011.0561
edition http://dx.doi.org/10.17192/z2011.0561
last_indexed 2011-09-13T23:59:59Z
building Medizin
publisher Philipps-Universität Marburg
title_alt Interferon regulatorische Faktoren 1 und 4 in der T Zell-vermittelten Immunantwort
url http://archiv.ub.uni-marburg.de/diss/z2011/0561/pdf/dajm.pdf
author Mahiny, Azita Josefine
publishDate 2011
era_facet 2011
description The transcription factor interferon regulatory factor (IRF) 1 is essential for T helper cell 1 differentiation. Hereby, the respective Irf1 knockout mouse displays a severe immune defect and has an Th2 directed immune status per se. This effect is measurable by increased production of interleukin-4, a Th2 associated cytokine, and increased levels of immunoglobulin E. By this, the mouse is incapable to cope with intracellular pathogens and eventually dies from infection (e.g. Leishmania major infection). Allergies are also mediated by a Th2 driven immune response, therefore the question raised, whether this knockout mouse would react stronger in case of an induced allergy. To address this topic, the murine OVA model for acute asthma was used. Interestingly and despite wide-ranging analyses, it could be shown in this thesis work that the IRF1 deficiency did not result in a more severe asthma pathology. The herein presented data urgently suggest to reconsider the long-standing paradigm of asthma as only being a Th2-diven disease. Newly dicovered Th cell subsets support this opinion. The Irf1 knockout mouse not only has a defect in Th cell differentiation, but also clearly shows the requirement of IRF1 in CD8 development. The numbers of CD8+ cells in the periphery is extremely reduced, mainly due to a thymic misregulation of MHC class I. In order to reveal cell-specific functions of IRF1, a conditionally targeted mouse for Irf1 was successfully generated in the framework of this thesis. This mouse will help to address a variety of questions regarding IRF1 function in a given setting. Beside IRF1, another factor of the IRF family, namely IRF4 is important for Th differentiation. IRF4 has functions in Th2, Th9 and Th17 cell development, and the IRF4 deficient mouse is completely resistant to murine experimental autoimmune encephalomyelitis, a model for the human disease multiple sclerosis, due to the total incapacity to generate Th17 cells producing IL-17. Surprising data are shown in this thesis, in which γδ T cells from Irf4 knockout mice are nevertheless totally capable of producing IL-17. The underlying mechanism was closer investigated, and although it was not possible to reveal the actual pathway (which is apparently different from the one triggering IL-17 production in Th17 cells), the possibilities were narrowed down by excluding many other apparently obvious pathways.
title Interferon regulatory factors 1 and 4 in T cell mediated immune modulation
title_short Interferon regulatory factors 1 and 4 in T cell mediated immune modulation
title_full Interferon regulatory factors 1 and 4 in T cell mediated immune modulation
title_fullStr Interferon regulatory factors 1 and 4 in T cell mediated immune modulation
title_full_unstemmed Interferon regulatory factors 1 and 4 in T cell mediated immune modulation
title_sort Interferon regulatory factors 1 and 4 in T cell mediated immune modulation
dewey-raw 570
dewey-search 570
genre Life sciences
genre_facet Life sciences
topic_facet Biowissenschaften, Biologie
format Dissertation
author2 Lohoff, Michael (Prof. Dr.)
author2_role ths
institution Hygiene u. Med. Mikrobiologie mit Medizinaluntersuchungsamt
thumbnail http://archiv.ub.uni-marburg.de/diss/z2011/0561/cover.png
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" A novel transcription factor, T-bet, directs Th1 lineage commitment. " Cell. 100(6):655-69. 2000 A novel transcription factor, T-bet, directs Th1 lineage commitment 2011-08-26 2011-09-06 Der Transkriptionsfaktor inteferon regulatory factor (IRF) 1 ist essentiell für die T Helfer (Th)-Zell-Differenzierung in Richtung Th1. Die entsprechende Knockout-Maus hat diesbezüglich einen so schwerwiegenden Defekt, daß sie per se eine Th2 gerichtete Immunantwort zeigt. Diese zeigt sich in einem erhöhten Level am Th2-Zytokin Interleukin (IL)-4 und einem erhöhten Immunglobulin E-Spiegel. Damit einhergehend ist diese Maus auch anfällig für intrazelluläre Pathogene, denen sie gegebenenfalls erliegt (z.B. eine Leishmania major-Infektion). Allergien zeigen ebenfalls eine Th2-gerichtete Immunantwort, daher lag die Vermutung nahe, daß die IRF1-defiziente Maus einen schweren Allergieverlauf aufweisen könnte. Im akuten murinen Asthmamodell, bei dem eine allergische Reaktion mittels Ovalbumin (OVA) provoziert wird, sollte diese Frage untersucht werden. Trotz breitgefächerter Analysen konnte in dieser Arbeit gezeigt werden, daß die IRF1 Maus erstaunlicherweise keine stärkere Pathologie entwickelt. Dieses Ergebnis macht besonders deutlich, daß die seit langem vorherrschende Meinung, daß Allergien, insbesondere Asthma, eine Th2-vermittelte Erkrankung sind, neu überdacht werden muß. Zur Zeit werden immer neue T helfer Subtypen beschrieben, die die hier gezeigten Ergebnisse weiter untermauern. Die IRF1 defiziente Maus weist auch einen Entwicklungsdefekt von CD8+ T Zellen auf, der deutlich macht, daß IRF1 auch andere Funktionen hat, die sich unabhängig von der T Helfer Zell-Differenzierung abspielen. In der Peripherie sind erheblich weniger CD8 positive Zellen zu finden, hauptsächlich weil im Thymus die MHCI-Präsentation fehlgeleitet ist. Um zellspezifische Funktionen von IRF1 aufzuklären, wurde im Rahmen dieser Arbeit eine für IRF1 konditionell getargetete Maus generiert, die sicherlich im Rahmen vielfältigster Fragestellungen hilfreich sein wird. Neben IRF1 hat IRF4 eine äquivalente Funktion in der Th2 Zelldifferenzierung, zusätzlich ist es aber ebenso wichtig für Th9 und Th17 Immunantworten. Im Fall der Th17 Zellen ist dieser Effekt derart drastisch, daß in der Irf4 Knockoutmaus keine Th17-Differenzierung stattfindet und die Maus im murinen Modell für Multiple Sklerose, der experimentellen autoimmunen Enzephalomylitis, für diese Krankheit vollständig resistent ist. Daher überraschte die in dieser Arbeit gezeigte IL-17 Produktion von IRF4 defizienten γδ T-Zellen. Obwohl der zugrundeliegende Mechanismus noch nicht aufgedeckt werden werden konnte, ist es dennoch möglich gewesen, im Rahmen dieser Arbeit verschiedene, naheliegende Signalwege auszuschließen und damit die Möglichkeiten stark einzugrenzen. http://dx.doi.org/10.17192/z2011.0561 2011-09-13 Interferon regulatorische Faktoren 1 und 4 in der T Zell-vermittelten Immunantwort opus:3910 2011 urn:nbn:de:hebis:04-z2011-05618 The transcription factor interferon regulatory factor (IRF) 1 is essential for T helper cell 1 differentiation. Hereby, the respective Irf1 knockout mouse displays a severe immune defect and has an Th2 directed immune status per se. This effect is measurable by increased production of interleukin-4, a Th2 associated cytokine, and increased levels of immunoglobulin E. By this, the mouse is incapable to cope with intracellular pathogens and eventually dies from infection (e.g. Leishmania major infection). Allergies are also mediated by a Th2 driven immune response, therefore the question raised, whether this knockout mouse would react stronger in case of an induced allergy. To address this topic, the murine OVA model for acute asthma was used. Interestingly and despite wide-ranging analyses, it could be shown in this thesis work that the IRF1 deficiency did not result in a more severe asthma pathology. The herein presented data urgently suggest to reconsider the long-standing paradigm of asthma as only being a Th2-diven disease. Newly dicovered Th cell subsets support this opinion. The Irf1 knockout mouse not only has a defect in Th cell differentiation, but also clearly shows the requirement of IRF1 in CD8 development. The numbers of CD8+ cells in the periphery is extremely reduced, mainly due to a thymic misregulation of MHC class I. In order to reveal cell-specific functions of IRF1, a conditionally targeted mouse for Irf1 was successfully generated in the framework of this thesis. This mouse will help to address a variety of questions regarding IRF1 function in a given setting. Beside IRF1, another factor of the IRF family, namely IRF4 is important for Th differentiation. IRF4 has functions in Th2, Th9 and Th17 cell development, and the IRF4 deficient mouse is completely resistant to murine experimental autoimmune encephalomyelitis, a model for the human disease multiple sclerosis, due to the total incapacity to generate Th17 cells producing IL-17. Surprising data are shown in this thesis, in which γδ T cells from Irf4 knockout mice are nevertheless totally capable of producing IL-17. The underlying mechanism was closer investigated, and although it was not possible to reveal the actual pathway (which is apparently different from the one triggering IL-17 production in Th17 cells), the possibilities were narrowed down by excluding many other apparently obvious pathways. Interferon regulatory factors 1 and 4 in T cell mediated immune modulation Philipps-Universität Marburg Mahiny, Azita Josefine Mahiny Azita Josefine ths Prof. Dr. Lohoff Michael Lohoff, Michael (Prof. Dr.)
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