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）是一种中枢神经系统慢性炎症性疾病。MS的发病机制需要自身反应性CD4+ T效应细胞的参与，如T辅助（Th）1淋巴细胞，其特征是产生干扰素- γ，以及最近发现的Th17细胞，根据其产生细胞因子白介素(IL)-17而命名。尽管近年来在这些T细胞的分化需求和功能特征方面取得了很大进展，但决定其致病性的分子基础仍然不明确。深入了解控制淋巴细胞致病性的机制对于实现自身免疫性疾病的有效治疗干预至关重要。因此，提出的项目旨在提供对具有致脑潜能的淋巴细胞形成的分子机制的见解，并将增加对参与表型分化和特化的因素的理解。本提案的重点是转录因子T-bet，它在炎症反应中控制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，这表明它在th生物学中起着额外的作用。th1相关转录因子T-bet对产生il -17细胞的脑致生性的影响将通过MS动物模型——实验性自身免疫性脑脊髓炎（EAE），通过两种方法进行研究。首先，基于Cre/ loxp的il -17特异性缺失T-bet的报告小鼠模型将揭示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-sequencing （RNA-Seq）将使我们能够深入研究T-bet在Th17细胞中启动的分子机制。

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.