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Rôle du TNFR2 exprimé à la surface des lymphocytes T régulateurs dans l’inflammation dépendante du TNFα

Abstract : Rheumatoid arthritis (RA) is a chronic inflammatory disease with unknown etiology. In this pathology, inflammation is mainly dependent on the pro-inflammatory cytokine TNFα. This molecule acts through two receptors: TNFR1 and TNFR2. TNFR1 is expressed on almost all cell types. Activation of this pathway mainly leads to cell death and is often associated with pro-inflammatory response. In contrast, TNFR2 is expressed on immune, epithelial and neuronal cells. Activation of TNFR2 signaling triggers cellular survival and cell proliferation. Furthermore, TNFR2 pathway is associated with anti-inflammatory mechanisms. Regulatory T cells (Treg) play a pivotal role in the control of inflammation and are defective in RA. They are characterized by the expression of transcriptional factor Forkhead box P3 (FoxP3). Tregs express both TNFα receptors and are able to inhibit inflammatory cells, specifically effector T cells using various immunosuppressive mechanisms. Treg expressing TNFR2 have been identified as the most suppressive Treg population. The aim of this study was to elucidate the role of TNFR2+ Tregs in TNFα mediated - inflammation by. Firstly, we have shown that TNFα-TNFR2 signaling on Tregs increased their proliferation and helped to maintain FoxP3 expression. Moreover, TNFR2 expression was associated with increased Treg stability. These results could explain the potential role of TNFR2+ Tregs in control of TNFα mediated - inflammation. To confirm this hypothesis, we demonstrated, in two models of inflammation mediated by TNFα (arthritis and psoriasis), that TNFR2+ Tregs play a major role in the control of inflammation. Finally, our experiments in RA patients highlighted that anti-TNFα treatments increased circulating TNFR2+ Treg frequency in responder RA patients. By demonstrating the major role of TNFR2+ Tregs in resolution of inflammation, our work paves the way for therapies targeting more specifically TNFα/TNFR system to cure RA and others TNFα - mediated pathologies.
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François Santinon. Rôle du TNFR2 exprimé à la surface des lymphocytes T régulateurs dans l’inflammation dépendante du TNFα. Rhumatologie et système ostéo-articulaire. Université Sorbonne Paris Cité, 2018. Français. ⟨NNT : 2018USPCD006⟩. ⟨tel-02561050⟩

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