Opposing activities of IRF1 and IRF4 in regulating the Il9 locus in Th9 cells

The T helper (Th)9 cell transcriptional network is formed by an equilibrium of signals induced by cytokines and antigen presentation. Positive regulators including interferon regulatory factor (IRF)4 promote expression of the key cytokine interleukin (IL)-9 in Th9 cells, whereas interferon (IFN)-γ r...

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Bibliographic Details
Main Author: Campos Carrascosa, Lucia
Contributors: Huber, Magdalena (Prof. Dr.) (Thesis advisor)
Format: Dissertation
Language:English
Published: Philipps-Universität Marburg 2017
Hygiene u. Med. Mikrobiologie mit Medizinaluntersuchungsamt
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Summary:The T helper (Th)9 cell transcriptional network is formed by an equilibrium of signals induced by cytokines and antigen presentation. Positive regulators including interferon regulatory factor (IRF)4 promote expression of the key cytokine interleukin (IL)-9 in Th9 cells, whereas interferon (IFN)-γ represses IL-9 production. Here we show that the IFN-γ-triggered inhibition of IL-9 is mediated via IRF1 in human and mouse Th9 cells. Thereby, IRF1 opposes IRF4 functions and dose-dependently limits IRF4-driven Il9 promoter activity and IL-9 production. Abundance of IRF1 correlates with decreased IRF4 occupancy pointing to IRF1/IRF4 binding competition at the Il9 locus. In addition, IRF1 binding associates with reduced permissive histone acetylation and accordingly with diminished RNA polymerase II (pol II) recruitment at the Il9 locus. Furthermore, IFN-γ-induced IRF1 shifts the Th9 transcriptome towards an IFN/Th1-like gene signature. Consistently, the absence of IRF1 leads to increased pathogenicity of IFN-γ-treated Th9 cells in allergic airway disease (AAD). Thus, we identified the ratio between IRF1 and IRF4 as a key factor for balancing Th9 differentiation. Hence, interfering with the IRF1/IRF4 equilibirium might prove useful for asthma therapy.
Physical Description:93 pages.
DOI:https://doi.org/10.17192/z2017.0598