Understanding the regulation of IL-17 producing lymphocytes by the cytokine TGF (beta).

Th17细胞是CD4+辅助性T细胞的一种，已被证明是胃肠道和皮肤等屏障表面免疫的关键介质。在这些部位，这些辅助性T细胞参与免疫监视和屏障完整性的维持，因此对细菌和真菌感染具有中介保护作用。然而，Th17细胞也被证明可以促进异常炎症，并且在包括多发性硬化症、类风湿性关节炎和牙周炎(后者是实验室特别关注的)等过多的自体炎症条件下是病理的关键驱动因素。了解Th17细胞的这些积极和消极作用一直是许多研究的目标，越来越清楚的是，Th17细胞表现出广泛的功能多样性和可塑性。事实上，最近的研究已经确定了将驱动组织炎症和损伤的“致病”Th17细胞与具有屏障保护作用的“稳态”Th17细胞区分开来的基因特征。然而，驱动这些不同命运和Th17细胞功能的细胞外信号的获得仍然知之甚少，但这将预示着一项重要的进展，使选择性抑制致病Th17细胞成为治疗现实。这个项目的目的是从机械上了解Th17细胞如何整合局部信号，以进行训练，以承担“内稳态”和“致病”功能。该项目将使用复杂的转基因小鼠模型，同时检查人类组织样本中的Th17细胞，以前所未有的深入了解Th17细胞如何获得独特的功能能力。通过在免疫学、分子生物学、生物信息学和转化医学领域的操作，学生将获得对跨学科方法的价值的重要理解，并接受尖端免疫学技术的培训，包括：体内炎症模型、免疫细胞体外培养、多色流式细胞术和全基因组转录图谱。最终，该项目旨在为新疗法的开发提供信息，使其能够精确操纵Th17细胞。此外，产生的数据将改善我们目前对Th17细胞生物学的理解，提供对Th17细胞功能异常所涉及的过多疾病的洞察。

Th17 cells are a lineage of CD4+T-helper cells that have been shown to be critical mediators of immunity at barrier surfaces such as the gastrointestinal tract and skin. At these sites these T-helper cells participate in both immune surveillance and maintenance of barrier integrity and therefore mediate protection against both bacterial and fungal infections. However, Th17 cells have also been shown to promote aberrant inflammation and are key drivers of pathology in a plethora of auto-inflammatory conditions, including multiple sclerosis, rheumatoid arthritis, and periodontitis (the latter a particular focus in the lab). Understanding these positive and negative roles for Th17 cells has been the aim of much research and it is becoming increasingly clear that Th17 cells exhibit both extensive functional diversity and plasticity. Indeed, recent studies have identified gene signatures that distinguish "pathogenic" Th17 cells, which drive tissue inflammation and damage, from barrier protective "homeostatic" Th17 cells. However, the extracellular signals that drive acquisition of these disparate fates and functions of Th17 cells remain poorly understood, but would herald an important advance allowing the selective inhibition of pathogenic Th17 cells to become a therapeutic reality. The aim of this project is to mechanistically understand how Th17 cells integrate local signals to be trained to take on "homeostatic" and "pathogenic" functions. This project will employ sophisticated transgenic mouse models, alongside examination of Th17 cells from human tissue samples, to generate unprecedented insight into how Th17 cells acquire distinct functional capabilities. By operating across immunology, molecular biology, bioinformatics and translational medicine fields the student will gain vital understanding of the value of interdisciplinary approaches and be trained in cutting-edge immunology techniques including: in vivo models of inflammation, in vitro culture of immune cells, multicolour flow-cytometry, and genome-wide transcriptional profiling. Ultimately, this project aims to inform development of novel therapeutics to that will allow precise manipulation of Th17 cells. Moreover, data generated will improve our current understanding of Th17 cell biology, providing insight into the plethora of disorders in which aberrant Th17 cell function is implicated.