Genetische Analyse des Mechanismus der ubiquitinilierungsabhängigen Kontrolle der Signaltransduktion durch den T-Zell Rezeptor (The genetic analysis of the mechanism of the ubiquitination-dependent control of T cell receptor signalling)

T细胞的发育和激活是由T细胞抗原受体信号控制的。MHC多肽配体与TCR和CD4或CD8共受体结合后，可诱导src家族蛋白酪氨酸激酶(src-PTK)的激活，进而组装TCR依赖的信号转导链。TCR依赖信号的强度在很大程度上取决于TCR-CD3信号复合体的表面表达水平和src-PTK、Lck和Fyn的细胞内表达水平。MHC多肽配体与TCR结合后，TCR-CD3和srcPTKs泛素化和下调。这一过程被认为在设定T细胞激活阈值以防止T细胞过度激活方面发挥了重要作用。配体诱导TCR和src-PTKs泛素化的机制尚不清楚。该项目的目的是了解TCR-CD3和src-PTK泛素化的机制以及这一过程在T细胞激活和发育中的作用。

The development and activation of T cells is governed by signals derived from T cell antigen receptor. Binding of the MHCpeptide ligands to TCR and CD4 or CD8 co-receptors induces the activation of src-family protein tyrosine kinase (src-PTK) followed by assembly of the functional TCR-dependent signal transducing chain. The strength of the TCR dependent signal is largely detemined by the surface expression levels of TCR-CD3 signalling complex and intracellular expression levels of src-PTK Lck and Fyn. Binding of the MHC-peptide ligand to TCR is followed by ubiquitination and down-regulation of TCR-CD3 and srcPTKs. This process is supposed to play an important role in setting up the threshold for T cell activation at levels preventing the hyperactivation of T cells. The mechanisms of ligand-induced ubiquitination of TCR and src-PTKs are poorly understood. The aim of the proposed project is to understand the mechanism of ubiquitination of TCR-CD3 and src-PTK and the role of this process in T cell activation and development.