The role of T cell SMAD7 in cellular immunity and in the regulation of autoimmune inflammation in the central nervous system

细胞因子TGF-β是T细胞功能的主要调节因子。我们假设下调Smad7 （TGF-β的细胞内抑制剂）可以抑制自身免疫性炎症。在此之前，我们已经在多发性硬化症动物模型中证明了T细胞特异性smad7缺失的小鼠减少了疾病和中枢神经系统炎症。有趣的是，疾病易感性与Th1反应相关，而与Th17反应无关。现在，我们打算研究TGF-β和Smad7如何在细胞和分子水平上调节T细胞分化和效应功能，以及这对实验感染模型的影响。因此，我们想要分析T细胞中的TGF-β信号是通过Smad途径还是通过其他途径传递的，以及Smad7是否具有独立于其阻断TGF-β信号传导能力的功能。此外，我们想要表征T细胞和抗原提呈细胞的相互作用是如何被异常TGF-β信号调节的。最后，我们想要研究smad7缺失如何改变对细菌和真菌感染的易感性。总之，该项目的目的是更好地了解Smad7在T细胞中的调节和功能，这将促进旨在抑制炎症的特异性免疫治疗的发展。

The cytokine TGF-β is a master regulator of T cell function. We hypothesized that downregulation of Smad7, the intracellular inhibitor of TGF-β, would dampen autoimmune inflammation. Previously, we have shown that mice with a T cell-specific Smad7-deletion have reduced disease and CNS inflammation in an animal model of multiple sclerosis. Interestingly, disease susceptibility correlated with Th1 but not Th17 responses. Now, we intend to examine how TGF-β and Smad7 regulate T cell differentiation and effector function on a cellular and molecular level and which consequences this has for experimental infection models. Therefore, we want to analyse whether TGF-β signals in T cells are exclusively transmitted through the Smad pathway or by alternative pathways and if Smad7 has functions independent from its ability to block TGF-β signalling. Furthermore, we want to characterize how the interaction of T cells and antigen presenting cells is modulated by aberrant TGF-β signalling. Finally, we want to examine how a Smad7-deletion changes susceptibility to infection with bacteria and fungi. In summary, the objective of this project is to better understand the regulation and function of Smad7 in T cells, which will facilitate the development of specific immune-based therapeutics aiming to dampen inflammation.