线粒体代谢与NKT细胞的功能研究

Chronic diseases are critically linked to alterations in cellular metabolism. It has been shown that cellular metabolism regulates development and functions of immune cells. Thus, during the progression of diseases, changes of nutrients, oxygen and metabolites would alter the fates and functions of local immune cells. However, the cellular and molecular mechanisms are still unclear. Exploring the underlying mechanisms would help to understand pathogenesis of diseases and develop therapeutic strategies. NKT cells are tissue resident and innate-like T cells, which participate the first line of body defense and share limited similarity to conventional T cells at location, phenotype and effector functions. Our previous studies indicate dynamic alterations in NKT cell functions during the progression of diseases, which are important for disease development. Whether the functional alterations are related to changes of cellular metabolism remains unclear. Here, we would demonstrate the cellular metabolism in NKT cells, and investigate the mechanisms by which mitochondrial metabolism regulates NKT cell functions. Further more, we would address the crosstalk between tumor cells and NKT cells by showing the influences of tumor microenvironments on metabolism and functions of NKT cells.

多种慢性疾病的发生都与细胞代谢的改变相关。胞内代谢参与对免疫细胞发育分化和功能的调控。疾病发生过程往往伴随着组织中营养分子、氧浓度、代谢产物含量的变化，从而影响了免疫细胞的命运和功能。然而，具体调控机制仍不清楚。对这一问题的阐释将有利于我们理解疾病的病理机制并寻找新的治疗方案。NKT细胞作为组织驻留的固有样T淋巴细胞参与免疫防疫的第一线，与常规T细胞在表型、功能、效应方式及定位等方面都存在明显差异。我们发现，疾病组织NKT细胞功能的动态变化与疾病发生发展密切相关。胞内代谢也可能是调控NKT细胞命运和功能的关键因素。目前，代谢对NKT细胞功能的调控机制尚缺乏研究。我们拟进一步对NKT细胞的代谢与功能间的关系进行阐释，揭示NKT细胞的代谢途径以及线粒体代谢对其功能的调控机制，并探讨肿瘤微环境对其代谢和功能的调控机制。

胞内代谢参与对免疫细胞发育分化和功能的调控。疾病发生过程往往伴随着组织中营养分子、氧浓度、代谢产物含量的变化，从而影响了免疫细胞的命运和功能。iNKT细胞作为组织驻留的固有样T淋巴细胞参与免疫防疫的第一线，与多种疾病包括肿瘤的发生发展密切相关。代谢对iNKT细胞功能的调控机制及与肿瘤的关系仍不清楚。本项目研究了代谢、线粒体对iNKT细胞功能的调控机制以及与肿瘤内iNKT细胞功能障碍间的关系。项目按计划执行，完成了既定目标，揭示了线粒体、氧化磷酸化、糖代谢、脂合成对iNKT细胞的功能调控机制，发现了肿瘤内iNKT细胞功能障碍的细胞分子机制及其与代谢的关系，为干预iNKT细胞功能促进抗肿瘤免疫提供了新靶点和新策略。相关研究成果发表论文8篇，其中PNAS以上论文5篇。