共抑制分子Tim3调控糖代谢介导脓毒症时T细胞功能障碍的机制研究

Sepsis causes millions of deaths globally each year. Dysfunction of T lymphocytes is the major cause of immunosuppression during sepsis.It is known that metabolism fundamentally underpins T cell function. Glucose metabolism is critical to the activation and differentitaion of T cell into its functioning status.Interestingly, our previous study found that glucose metabolism changed in T cells during sepsis. However, mechanisms that link glucose metabolism to T cell function are poorly understood. Our later research indicated that T Cell Ig- and mucin-domain-containing molecule-3 (Tim3) blockade could improve T cell function and restore its glucose metabolism partly. We then propose that Tim3 might be a critical molecure involved in T cell glucose metabolism during sepsis. Our current program was designed to illuminate the role of Tim3 in T cell glucose metabolism regulation from bench to beside, including septic patients,in vitro T cell study, and Tim3 gene knockout mice. The following scientific questions raised need to be resolved. First, the role of glucose metabolism abnormality in T cell dysfunction during sepsis will be illustrated. Second, the role of Tim3 in T cell glucose metabolism regulation in sepsis will be explored. Third, the potential pathways involved in Tim3 mediated T cell glucose metabolism in sepsis will be investigated. Collectively, through the research into the glucose metabolism of T cells during sepsis, our program will provide valuable insights into the mechanisms of sepsis and might raise a new potential therapeutic area in future.

免疫抑制是导致脓毒症患者死亡重要原因，T细胞功能障碍是其重要机制。已知，共抑制分子Tim3通过负性调控作用抑制T细胞功能。能量代谢是调控细胞功能的基础环节，糖代谢途径是维持T细胞功能的重要方式。我们前期研究发现，脓毒症患者免疫细胞出现糖代谢水平异常，其调控方式及病生机制值得深入研究。我们进一步实验表明，阻断Tim3可改善脓毒症小鼠T细胞功能；Tim3-/-脓毒症小鼠T细胞糖代谢水平较野生型显著改善。我们推测：Tim3调控细胞糖代谢途径介导了脓毒症时T细胞功能障碍。本项目将从临床患者、离体细胞及转基因动物，探索脓毒症T细胞功能与糖代谢水平异常的关系；Tim3调控脓毒症T细胞糖代谢异常的作用方式；基于色谱质谱技术、激酶通路上下游途径探索Tim3调控T细胞糖代谢的机制。本研究从细胞糖代谢这一新角度着眼，将加深对脓毒症病理生理机制认识，为通过Tim3防治脓毒症提供实验依据。

脓毒症是临床棘手难题，免疫抑制是导致脓毒症患者死亡的重要原因，免疫抑制的一个重要表现是T 细胞功能受损。能量代谢是调控细胞功能的重要环节，糖代谢途径是维持T细胞功能的重要能量代谢方式。我们前期研究发现，脓毒症患者免疫细胞糖代谢异常，其调控方式值得深入研究。阻断Tim3可改善脓毒症小鼠CD4+T和CD8+T细胞功能，部分恢复糖代谢水平。本项目从临床脓毒症患者、离体细胞及转基因动物三个层面，系统探索以下几个科学问题：脓毒症时T细胞糖代谢水平与细胞功能异常的关系；Tim3在调控脓毒症时T细胞糖代谢改变中的作用。本研究证实了Tim3对脓毒症时CD4+T细胞糖酵解具有调控作用，还可影响T细胞功能；Tim3-/-的脓毒症小鼠CD4+T细胞糖酵解和氧化磷酸化均受到抑制。Tim3能抑制健康志愿者外周血CD4+T细胞产生IFN-γ，还抑制葡萄糖的转运以及利用，减少糖酵解相关关键酶表达，还能减少乳酸产生，抑制正常人CD4+T细胞糖酵解和氧化磷酸化水平，能调控细胞糖代谢及细胞功能。总之，本研究基于Seahorse能量代谢检测等手段，探讨Tim3调控 T 细胞糖代谢异常的具体机制。本研究结果有助于加深对脓毒症病理生理机制的认识，研究成果为通过Tim3分子治疗脓毒症提供新的理论和实验依据。