Another “key” to solving the mystery of memory T cell memory


Schematic diagram of research results (Photo courtesy of the research group)

On December 6, Nature Immunology, a top international immunology journal, published a new study by Professor Huang Bo’s research group from the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and the School of Basic Medical Sciences of Huazhong University of Science and Technology. This study reveals that urea cycle metabolism is important for maintaining the development and long-term survival of memory T cells, and explains the fundamental immunological problem of T cell memory formation from a completely new metabolic pathway.

As we all know, the body resists the invasion of foreign substances through a variety of mechanisms, and memory T cells can quickly remove pathogens or tumors by virtue of their rapid proliferation and activation when encountering the same antigen, thereby limiting the further development of the disease. This feature makes memory T cells also become the main force of anti-tumor immunity, which is also of great significance for preventing tumor recurrence.

Unfortunately, scientists at home and abroad have not yet analyzed the reasons why memory T cells maintain a long lifespan.

“Memory T (Tm) cells belong to a typical class of long-lived cells, which can survive in the body for months to years or even life, and are the basis for vaccine protection, tumor immunotherapy, and antiviral infection.” To this end, Huang Bo’s research group has long been working to reveal the key metabolic characteristics of memory T cells to maintain long life.

In 2018, the research group found that the long-term survival of memory T cells is related to the unique metabolic mode of gluconeogenesis-glycogen metabolism, Tm promotes glycogen synthesis through the key rate-limiting enzyme phosphoenol pyruvate carboxykinase PCK1 that highly expresses the gluconeogenesis pathway, and produces reduced NADPH through the pentose phosphate pathway, maintains high levels of reducing glutathione, and timely removes oxygen free radicals in the cell, thereby maintaining the long-term survival of memory T cells.

Tm is derived from effector T cells, why is the expression of PCK1 different?

In order to answer this scientific question, Huang Bo’s group continued to conduct in-depth research and found that there is ketone metabolism in memory T cells, which is different from the conventional energy supply of ketone bodies, ketone metabolism in Tm promotes epigenetic modification of histones through β-hydroxybutyric acid to mediate the high expression of PCK1, which plays an important role in the function maintenance and long-term survival of memory T cells, and the relevant research results were published in Nature Cell Biology in 2018 and 2020.

Huang Bo told China Science News that cells need to use the energy molecule ATP to maintain life activities. Glucose and fatty acid oxidation are the main sources of ATP production. In addition, amino acids can also be oxidized after deamination to provide or regulate energy production. However, reactive oxygen species (ROS) and ammonia (NH3) are also unavoidably produced as by-products of ATP production in cells, and both substances are cytotoxic and impair cell lifespan. Therefore, long-lived cells must utilize efficient mechanisms to remove ROS and ammonia to prolong survival.

In previous studies, the team has revealed how memory T cells clear ROS, but whether CD8+ T cells can remove toxic ammonia through metabolism remains an unsolved mystery.

Huang Bo said that the deamination of amino acids is the main source of intracellular ammonia, mainly through two steps: the first step is transamination-mediated production of glutamate or glutamine, and the second step is the deamination of glutamate or glutamine. It is generally believed that ammonia is processed in the liver through the urea cycle, which is absorbed by hepatocytes from the peripheral cycle and catalyzed ammonia and bicarbonate (HCO3-) using carbamoyl phosphate synthetase-1 (CPS1) to form carbamoyl phosphate (CP) in mitochondria. CP then reacts with ornithine to produce citrulline via ornithine carbamoyl phosphotransferase (OTC). Citrulline then enters the cytoplasm, where arginine is generated by combining arginine succinate synthase 1 (ASS1) with aspartic acid, which is then metabolized by arginine lyase (ASL) to arginine and fumarate and finally arginase 1 (ARG1) hydrolyzes arginine to ornithine and urea, and finally ornithine enters the mitochondrial formation cycle.

However, the traditional concept of urea cycle only occurs in the liver, but the researchers have found a different way to prove for the first time that the urea cycle exists in memory T cells and plays an important function by constructing in vivo adoptive models of specific antigen memory T cells, isotope tracing technology and ultra-high-resolution liquid mass spectrometry, and verified that urea cycles are necessary for Tm cell memory maintenance through a series of animal models and in vitro mechanism analysis.

In subsequent studies, the researchers further found that unlike the traditional urea cycle that produces urea through arginase 1, CD8+ Tm cells use arginase 2 localized to mitochondria to catalyze arginine production of urea, and further investigated the entry and exit of arginine and urea in and out of mitochondria through SLC25A29 and SLC14A1, respectively; In-depth mechanistic studies have also found that in addition to the urea cycle, CD8+ Tm cells also use the citrulline cycle for ammonia dehydration and work in combination with the urea cycle.

In addition, the researchers also used a variety of animal models to verify that gene expression of Cps1, a key enzyme in the urea cycle, is essential for ammonia processing and memory maintenance in Tm cells, and used epigenetic means to find that β-hydroxybutyrylation in the Cps1 transcription promoter region is the key to inducing Cps1 expression. Finally, in the in vivo tumor treatment model, Tm cells with high expression of Cps1 also showed more efficient anti-tumor function, which provided a new metabolic regulation idea for T cell infusion immunotherapy, which has clear clinical transformation significance.

“This research will enable us to elucidate the mechanism of long-term survival of Tm cells from a new metabolic perspective, and will provide a new way of thinking and transformation of T cells against tumors.” Huang Bo said.

It is reported that this research work has been supported by the National Natural Science Foundation of China (81788101, 82071864, 82150103) and the Medical and Health Science and Technology Innovation Project of the Chinese Academy of Medical Sciences (2021-I2M-1-021). Associate Professors Tang Ke and Zhang Huafeng, School of Basic Medical Sciences, Huazhong University of Science and Technology, and Deng Jinghui, a doctoral student, are the co-first authors of the paper, and Huang Bo is the corresponding author of the paper. (Source: Zhang Siwei, China Science News)

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