近期研究证实，T细胞功能耗竭可能在活动性结核发病中发挥重要作用。T细胞功能耗竭表现为T细胞增殖和分泌细胞因子能力下降，以及共抑制分子PD-1等持续表达上调；其中高表达转录因子T-bet的T细胞具有功能逆转潜能。TIGIT是新一代的共抑制分子，TIGIT/PVR轴参与负向免疫调控。我们前期研究发现，活动性结核患者存在CD8+T细胞功能耗竭，且结核特异性T-bet（high）CD8+T细胞中TIGIT的表达显著升高。因此，我们推测TIGIT/PVR轴可介导结核特异性CD8+T细胞功能耗竭及其逆转。本课题拟通过体外实验体系，探讨体外阻断TIGIT/PVR轴对结核特异性T-bet（high）CD8+T细胞功能的逆转作用及其机制；在动物感染模型中，探讨体内阻断TIGIT对机体清除结核菌、以及对CD8+T细胞功能和预后的影响，从而为开发以TIGIT/PVR轴为靶位的新型抗结核免疫治疗方法奠定基础。

Recent studies indicate that T cell exhaustion may have key role in the development of active tuberculosis. T cell exhaustion develops as a step-wise loss of proliferation, cytokine production，and it is characterized by over-expression of co-inhibitory receptors, such as PD-1. Exhausted T cell subset with high transcription factor T-bet expression can be reinvigorated by co-inhibitory pathway blockade. TIGIT is a recently identified T cell co-inhibitory receptor, and TIGIT/PVR axis negatively regulates the immune function. Our previous data confirmed the CD8+T cell exhaustion in active TB patients, and TIGIT expression was significantly up-regulated on T-bet (high) CD8+T cells in TB patients. We hypothesize that TIGIT/PVR axis mediates T-bet（high）CD8+T cell exhaustion and its restore during Mycobacterium tuberculosis (Mtb) infection. In this project, we will further study the mechanism of exhaustion and its functional restoration in vitro; we will explore the impact of in vivo TIGIT blockade on Mtb clearance, CD8+T cell function and disease outcome in susceptible infected mice model. This project is expected to contribute to the development of new immunotherapy of TB based on TIGIT/PVR axis.