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Role of the transcription factor c-Maf in regulating inflammatory immune responses

par Hussein, Hind
Président du jury Vanhamme, Luc
Promoteur Andris, Fabienne
Co-Promoteur Leo, Oberdan
Publication Non publié, 2020-10-16

Thèse de doctorat

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Résumé :

Regulatory T cells (Treg) are a suppressive subset of helper T cells that controls immune responses using a variety of mechanisms. Despite initially being thought of as a homogenous population, Treg cells were recently found to adapt their function to their environment and acquire specialized phenotypes depending on their tissue of residence. The molecular mechanisms underlying this functional and tissular adaptation remain to be fully elucidated.In the course of this work, we studied the role of transcription factor c-Maf in the differentiation and the function of Treg cells. For this, we used a murine model invalidated for c-Maf specifically in Treg cells. Transcription factor c-Maf is preferentially expressed by intestinal Treg cells, particularly among the RORγt+ Treg subset, which controls immune responses directed towards the gut microbiota. We have shown that the differentiation of RORγt+ Treg cells results from the integration of multiple environmental signals, highlighting the plasticity of Treg specialization. Furthermore, we have shown that c-Maf is required for the differentiation of RORγt+ Treg cells as well as the expression of the anti-inflammatory cytokine IL-10 by intestinal Treg cells, thus endowing Treg cells with the ability to control homeostatic Th17 responses in the intestine. Mice deficient for c-Maf in Treg cells exhibit an exacerbated Th17 response and spontaneously develop colitis. However, c-Maf-deficient mice develop fewer polyps in a model of colitis-associated colon cancer. This suggests that c-Maf expression in Treg cells plays a beneficial role on intestinal homeostasis at steady state, but is detrimental in a tumoral context.Our results allow a better understanding of the mechanisms involved in the specialization of intestinal Treg cells. The knowledge of these mechanisms is crucial for the identification of new therapeutic targets in the context of inflammatory bowel disease and colon cancer.