The project seeks to reveal the molecular mechanisms controlling the pathogenicity of lymphocytes in multiple sclerosis. For this, mRNA-Seq and a Cre/loxP-based mouse model will be used to analyse the impact of the Th1-associated transcription factor T-be

多发性硬化症(MS)是一种慢性中枢神经系统炎症性疾病。MS的发病机制需要自身反应性的CD4+T效应细胞的参与，如以产生干扰素-伽马为特征的辅助性T细胞(Th)1，以及最近发现的Th17细胞，根据其产生的细胞因子白细胞介素17(IL-17)命名。尽管近年来在这些T细胞的分化要求和功能特性方面取得了很大进展，但决定其致病性的分子基础仍然不清楚。深刻而深入地了解控制淋巴细胞致病性的机制对于实现对自身免疫疾病的有效治疗干预是至关重要的。因此，拟议的项目旨在为形成具有脑生成潜力的淋巴细胞的分子机制提供见解，并将增加对涉及表型分化和特化的因素的理解。这项建议的重点是转录因子T-bet，它在炎症反应过程中控制Th1细胞生物学的多个方面。有趣的是，T-bet也在Th17细胞中表达，这表明在Th生物学中还有一个额外的作用。利用实验性自身免疫性脑脊髓炎(EAE)--一种多发性硬化症的动物模型，将通过两种方法研究Th1相关转录因子T-bet对IL-17产生细胞的脑原性的影响。首先，基于Cre/loxP的报告小鼠模型具有IL-17特异性的T-bet缺失，将揭示T-bet在体内产生IL-17的细胞中的功能。其次，高通量测序技术--mRNA测序(RNA-Seq)将使深入研究T-bet在Th17细胞中启动的分子机制成为可能。

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. The pathogenesis of MS requires the involvement of self-reactive CD4+ T effector cells, such as T helper (Th)1 lymphocytes, characterised by the production of interferon-gamma, and the recently discovered Th17 cells, named according to their production of the cytokine interleukin (IL)-17. Although great progress has been made in recent years with respect to the differentiation requirements and functional characteristics of these T cells, the molecular basis determining their pathogenicity remains ill defined. A profound and in depth knowledge of the mechanisms controlling the pathogenicity of lymphocytes is essential for the path towards effective therapeutic intervention in autoimmune disorders. Therefore, the proposed project aims to provide insights into molecular mechanisms that shape lymphocytes with an encephalitogenic potential and will increase the understanding of factors involved in phenotypic differentiation and specialisation. The focus of this proposal is on the transcription factor T-bet, which controls multiple aspects of Th1 cell biology during inflammatory responses. Interestingly, T-bet is also expressed in Th17 cells, suggesting an additional role in Th-biology. The impact of the Th1-associated transcription factor T-bet on the encephalitogenicity of IL-17-producing cells will be investigated using experimental autoimmune encephalitomyelitis (EAE), an animal model for MS, with two approaches. First, a Cre/loxP-based reporter mouse model with an IL-17-specific deletion of T-bet will reveal the function of T-bet in IL-17-producing cells in vivo. Second, the high-throughput sequencing technology mRNA-sequencing (RNA-Seq) will enable an in-depth study of the molecular mechanisms initiated by T-bet in Th17 cells.