Molecular mechanisms of phosphoantigen sensing by human gamma delta T cells

γ δ T细胞与T细胞和B细胞一起在脊椎动物中共同进化了约5亿年，并介导宿主防御微生物感染和肿瘤发生的关键方面。然而，它们感知靶细胞失调的分子机制在很大程度上还不清楚。该项目的重点是最普遍的人类T细胞亚群（T细胞），它代表外周血中高度普遍的先天性样群体，可以通过检测靶细胞中焦磷酸盐抗原（P-Ag）的升高水平，对细菌/分枝杆菌感染和癌细胞迅速作出反应。该项目将探测支撑该传感系统的关键分子相互作用，特别是T细胞受体与P-Ag“传感器”BTN 3A 1和直接配体BTN 2A 1的相互作用。将采用一系列方法，结构生物学和蛋白质建模方法，生物信息学分析，细胞免疫学测定，最后是免疫组织化学。这将为T细胞抗原识别提供全面的分子机制，并为未来合理开发T细胞在抗癌和抗微生物免疫治疗中的知识基础。

Gamma delta T-cells have co-evolved in vertebrates alongside T-cells and B cells for ~500 million years, and mediate critical aspects of host defense against microbial infection and tumourigenesis. However, the molecular mechanisms by which they sense target cell dysregulation are largely unclear. This project focusses on the most prevalent human Tcell subset ( T-cells), which represent a highly prevalent innate-like population in peripheral blood that can respond rapidly in bacterial/mycobacterial infection and to cancer cells, by detecting elevated levels of pyrophosphate antigens (P-Ag) in target cells. The project will probe key molecular interactions underpinning this sensing system, specifically T cell receptor interaction with the P-Ag 'sensor' BTN3A1 and a direct ligand BTN2A1. A range of approaches will be employed, structural biology and protein modelling approaches, bioinformatic analyses, cellular immunology assays, and finally immunohistochemistry. This should provide a comprehensive molecular mechanism for T cell antigen recognition, and a knowledge-base for future rational exploitation of T cell in anti-cancer and anti-microbial immunotherapy.