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Régulation des voies de signalisation des lymphocytes T par la protéine SAP et ses partenaires

Abstract : Immune responses need a coordinate involvement between different immune cell populations, as T and B cells, macrophages, dendritic cells or NK cells. Activation of these different cell populations is mediated by different receptors whose function is to initiate a signal transduction cascade. T cell activation, a crucial event in adaptive immune response, begins with T cell receptor (TCR) triggering. A large number of receptors can modulate T cell responses. Thus, cytokines, chimiokines and growth factors receptors, adhesion molecules and SLAM (for Signaling Lymphocyte Activation Molecule) family receptors regulate cell activation. Recent works have shown that SLAM receptors triggering induce their association with SAP (for SLAM-Associated Protein) family members and is vital for humoral immunity, NKT cell development and T CD8+ and NK cells cytotoxicity. Mutations in sh2d1a gene, which code for SAP, are responsible of X-linked Lymphoproliferative-1 (XLP-1) syndrome. Patients, who suffer from this syndrome, develop three main clinical manifestations: a fulminant infectious mononucleosis, dysgammaglobulinemia and lymphoproliferative syndromes.My thesis work was to study early steps of T cell activation and to understand how the SAP protein, associated with its partners, regulates these cellular mechanisms. Thus, my work was to identify new SAP partners, others than SLAM receptors, in order to better understand SAP function in T cell signaling.With a biochemical approach, my work has demonstrated that SAP directly associates with CD3 chain of TCR-CD3 complex, regulates cell signaling and cytokines secretion following TCR triggering. Finally, with a two-hybrid assay, we have identified the adhesion molecule Pecam-1 as a new SAP partner. Then, we have observed that SAP directly interacts with Pecam-1 to regulate T cell adhesion. During my thesis work, we have identified new cellular signaling pathways that are regulated by SAP and permit to better understand the cellular mechanisms that are affected when SAP is absent.
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Richard Proust. Régulation des voies de signalisation des lymphocytes T par la protéine SAP et ses partenaires. Cancer. Université Paris Sud - Paris XI, 2012. Français. ⟨NNT : 2012PA11T089⟩. ⟨tel-00914177⟩

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