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Étude de la régulation transcriptionnelle des lymphocytes Th9

Abstract : CD4 helper T cells support a wide range of functions due to their ability to differentiate into different effector subsets depending on the antigen encountered and the cytokine environment in which they are. Current knowledge on the differentiation of helper T cells highlights the existence of complex transcriptional networks specific to each T helper subset. In 2008, IL-9 secreting CD4 T cells (Th9) are identified as a new helper T cell subtype. Differentiated in the presence of IL-4 and TGF-β, Th9 cells secrete IL-9 and IL-21, and contribute to the development of autoimmune and allergic diseases. Th9 lymphocytes also exhibit strong anti-tumor properties.The transcriptional network of the Th9 cells results from a balance between the signaling pathways induced by the different cytokines required for its polarization. IL-4 allows activation of STAT6 and expression of GATA3 and IRF4, whereas TGF-β leads to activation of the Smad pathway and expression of the transcription factor PU.1. The IRF4 / BATF transcriptional module and the PU.1 factor are essential messengers for the development of Th9 cells and IL-9 secretion.IRF8 is a crucial transcription factor for the development of myeloid cells and B lymphocytes. Recently it appeared that IRF8 was involved in helper T subset polarization. Indeed, IRF8 limits the secretion of IL-17 by Th17 cells, as well as repressing the expression of Il4 and Il17 in Treg cells. Structurally close to IRF4, IRF8 interacts with cofactors such as PU.1 or BATF in order to regulate transcriptional activity.This work reveals that the IRF8 transcription factor contributes to the polarization of Th9 cells in vitro and in vivo. The TGF-β needed for Th9 cell differentiation activate Smad3 pathway which directly modulates the Irf8 expression. As in many cellular subtypes, the transcriptional function of IRF8 is dependent on these interaction partners. We show that in the presence of the transcription factors PU.1, IRF4 and BATF, IRF8 participates in a multiprotein complex essential for the induction of the Th9 cytokines, Il9 and Il21. We also demonstrate that in the presence of the ETV6 protein, IRF8 is able to form a complex responsible for the repression of Il4 expression. We underline the bivalent role played by IRF8 in the development of Th9 cells depending on its partners. Finally, expression of Irf8 is crucial for Th9 cells to exercise their antitumor functions.
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Etienne Humblin. Étude de la régulation transcriptionnelle des lymphocytes Th9. Médecine humaine et pathologie. Université Bourgogne Franche-Comté, 2017. Français. ⟨NNT : 2017UBFCI006⟩. ⟨tel-02093713⟩

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