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,...
Hygiene u. Med. Mikrobiologie mit Medizinaluntersuchungsamt
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|Summary:||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.|