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

细胞因子转化生长因子-β是T细胞功能的主要调节因子。我们假设，转化生长因子-β的细胞内抑制物Smad7的下调将抑制自身免疫性炎症。此前，我们已经证明，在多发性硬化症动物模型中，具有T细胞特异性Smad7缺失的小鼠可以减少疾病和中枢神经系统炎症。有趣的是，疾病易感性与Th1反应有关，但与Th17反应无关。现在，我们打算研究转化生长因子-β和Smad7如何在细胞和分子水平上调节T细胞分化和效应器功能，以及这对实验性感染模型有什么影响。因此，我们想要分析T细胞中的转化生长因子-β信号是通过Smad途径还是通过替代途径来传递，以及Smad7是否具有独立于其阻断转化生长因子-β信号的能力的功能。此外，我们想要描述T细胞和抗原提呈细胞之间的相互作用是如何受异常的转化生长因子-β信号调节的。最后，我们想研究Smad7缺失如何改变细菌和真菌感染的易感性。总之，本项目的目标是更好地了解Smad7在T细胞中的调节和功能，这将促进旨在抑制炎症的特定免疫疗法的发展。

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.