mTORC1调控PLZF在MAIT细胞抗结核免疫中的效应与机制

Tuberculosis (TB) is the world’s deadliest chronic contagion. Currently there is no effective treatment for this disease. It has been noted that the mucosal associated invariant T (MAIT) cells play an important role in the early anti-TB immune response. Targeted control of MAIT cells may be an effective way to improve vaccine efficacy and treat TB. However, little is known about the signal regulation mechanism of the TB specific MAIT cells. The research group is the first to carry out the study on the regulatory effects and mechanisms of PLZF by mTOC1 in MAIT cells-mediated immunity to Mycobacterium tuberculosis (MTB). After using MR1 tetramer to analyze MAIT cells in the peripheral blood of 133 active TB patients, our results showed that MAIT cells play an important role in the anti-TB immune response. On this basis, it is proposed to: (1) The anti-TB effect of MAIT cells is further determined by using MR1 tetramer; (2) Determine the regulatory effects of mTORC1 on the anti-TB activity of MAIT cells; (3) Clarify the mechanisms that the anti-TB activity of MAIT cells is controlled by mTORC1 which is activated by the PI3K-AKT and DAG-RasGRP1-Ras-ERK1/2 signaling pathway through regulating PLZF. The project provides ideas and potential therapeutic targets for the development of new TB immunotherapy.

结核是全球最致命的慢性传染病，尚无有效疗法。MAIT细胞在早期抗结核免疫反应中发挥关键作用，靶向控制MAIT细胞可能是改善疫苗功效和治疗结核病的有效方法。但目前对于结核特异性MAIT细胞的信号调控机制仍知之甚少。课题组率先开展mTORC1调控PLZF在MAIT细胞抗结核免疫中的效应与机制研究，前期利用MR1四聚体结合流式细胞术对133名活动性结核患者外周血MAIT细胞进行初步分析发现，MAIT细胞在结核感染免疫中发挥重要作用。在此基础上，拟：①利用MR1四聚体进一步明确MAIT细胞的抗结核作用；②确定mTORC1对MAIT细胞抗结核效应的调控作用；③阐明mTORC1在PI3K-AKT和DAG-RasGRP1-Ras-ERK1/2信号通路诱导下，通过调控PLZF调节MAIT细胞抗结核效应的机制。项目为开发新型抗结核免疫疗法提供思路和潜在治疗靶标。

结核病是全球最致命的慢性感染疾病。近年来，随着人口流动的增加、HIV与MTB伴发感染、以及耐药和多重耐药菌株的流行，全球结核病死灰复燃，呈现卷土重来之势。目前，结核病治疗仍以化疗为主，其疗程长，毒副作用大，病人服药依从性差，易产生耐药性。临床上唯一使用的卡介苗仅对预防儿童重症结核有效，对成人无直接保护作用。因此，开发新型抗结核免疫疗法已迫在眉睫！MAIT细胞在早期抗结核免疫反应中发挥至关重要的作用，靶向控制MAIT细胞可能是改善疫苗功效和治疗结核病的有效方法，但目前对其精确控制结核的信号调控机制仍然知之甚少。. 本项目利用MR1四聚体对活动性结核患者外周血MAIT细胞的抗结核效应及其机制进行了探讨，结果显示，①经结核抗原刺激后，与健康对照比较，活动性结核患者外周血MAIT细胞产生显著高水平的免疫活性，证实MAIT细胞在结核感染免疫中具有重要的抗结核作用；②抑制mTORC1信号后，可以显著降低活动性结核患者外周血MAIT细胞的抗结核效应；③mTORC1在PI3K-AKT信号通路诱导下，通过调控PLZF在核内定位从而调节MAIT细胞的抗结核效应。项目初步阐明了mTORC1调控PLZF在MAIT细胞抗结核免疫中的效应与机制，为开发新型抗结核免疫疗法提供思路和潜在治疗靶标。