Professor Huang’s team revealed the mystery of memory T cell formation and maintenance from metabolic pathway
Source：Huang Bo
2017-12-22
Professor Huang Bo’s team from Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences recently discovered that the critical mechanism of memory T cell formation and maintenance relies on gluconeogenesis-glycogen metabolism- pentose phosphate pathway. This research is published online in Nature Cell Biology as “A Pck1-directed glycogen metabolic program regulates formation and maintenance of memory CD8+ T cells”.
Activated CD8+ T cells can efficiently kill virus-infected cells as well as tumor cells. After its effect, a very small number of T cells survive and transform into memory T cells, which could be rapidly activated when challenged by the same antigen from virus or tumor cells. CD8+ memory T (Tm) cells are critical for protective immunity against infections and cancers. It is of great theoretical and clinical significance to elucidate the mechanism of CD8+ T cell memory formation and maintenance, which is still a fundamental problem to be uncovered. Using in vitro and in vivo models, Professor Huang's team found that CD8+ memory T cells utilize a very unique pattern of glucose metabolism formemory formation and maintenance. Glucose catabolism (glycolysis) is the basis energy source in cells. In contrast, glucose synthesis (gluconeogenesis) is the fundamental way to gain energy in nerve cells and red blood cells. Gluconeogenesis is thought to be mainly occurred in hepatocytes, however, this study found that gluconeogenesis is very active in memory T cells. This study showed that CD8+ Tm cells markedly upregulate cytosolic phosphoenolpyruvate carboxykinase (Pck1), the hub molecule regulating glycolysis, tricarboxylic acid cycle and gluconeogenesis, to increase glycogenesis via gluconeogenesis. The resultant glycogen is then channelled to glycogenolysis to generate glucose-6-phosphate and the subsequent pentose phosphate pathway (PPP) that generates abundant NADPH, ensuring high levels of reduced glutathione in Tm cells. Abrogation of Pck1–glycogen–PPP decreases GSH/GSSG ratios and increases levels of reactive oxygen species (ROS), leading to impairment of CD8+ Tm formation and maintenance. This article offers an opportunity to manipulate and improve T-cell-based cancer immunotherapy.
This work was supported by the CAMS Initiative for Innovative Medicine and the National Natural Science Foundation of China. Professor Xuetao Cao from Institute of Basic Medical Sciences and Professor Xiaofeng Qin from Suzhou Institute of Systems Medicine contributed a lot to this work.
Activated CD8+ T cells can efficiently kill virus-infected cells as well as tumor cells. After its effect, a very small number of T cells survive and transform into memory T cells, which could be rapidly activated when challenged by the same antigen from virus or tumor cells. CD8+ memory T (Tm) cells are critical for protective immunity against infections and cancers. It is of great theoretical and clinical significance to elucidate the mechanism of CD8+ T cell memory formation and maintenance, which is still a fundamental problem to be uncovered. Using in vitro and in vivo models, Professor Huang's team found that CD8+ memory T cells utilize a very unique pattern of glucose metabolism formemory formation and maintenance. Glucose catabolism (glycolysis) is the basis energy source in cells. In contrast, glucose synthesis (gluconeogenesis) is the fundamental way to gain energy in nerve cells and red blood cells. Gluconeogenesis is thought to be mainly occurred in hepatocytes, however, this study found that gluconeogenesis is very active in memory T cells. This study showed that CD8+ Tm cells markedly upregulate cytosolic phosphoenolpyruvate carboxykinase (Pck1), the hub molecule regulating glycolysis, tricarboxylic acid cycle and gluconeogenesis, to increase glycogenesis via gluconeogenesis. The resultant glycogen is then channelled to glycogenolysis to generate glucose-6-phosphate and the subsequent pentose phosphate pathway (PPP) that generates abundant NADPH, ensuring high levels of reduced glutathione in Tm cells. Abrogation of Pck1–glycogen–PPP decreases GSH/GSSG ratios and increases levels of reactive oxygen species (ROS), leading to impairment of CD8+ Tm formation and maintenance. This article offers an opportunity to manipulate and improve T-cell-based cancer immunotherapy.
This work was supported by the CAMS Initiative for Innovative Medicine and the National Natural Science Foundation of China. Professor Xuetao Cao from Institute of Basic Medical Sciences and Professor Xiaofeng Qin from Suzhou Institute of Systems Medicine contributed a lot to this work.
