Superantigen Mutant Activate the Fatty Acid and Mitochondrial Energy Metabolic Programs of CD8+ T Cells
The key factor to the successful tumor immunotherapy is full activation of CD8+ cytotoxic T cells. However, in clinical treatment, tumor cells always escape from the immune attack of CD8+ T cell through a variety of immunosuppressive pathways. T cells require a constant supply of energy metabolites to maintain normal immune function. In this process, mitochondria are the main organelle for intracellular oxidative phosphorylation and ATP synthesis. But, in the tumor microenvironment with nutrient-deficient condition, restriction of nutrient such as glucose and oxygen could impair the activities of CD8+ T cells, which leads to CD8+ T cells anergy or apoptosis. Therefore, reprogramming of CD8+ T cell energy supply through fatty acid catabolism and mitochondrial energy metabolism are feasible strategies for the successful cancer immunotherapy.
As a kind of promising T cell activators, superantigens and their mutants can stimulate powerful T-cell immune response and elicit potent cytotoxic effects to tumor cells. Recently, combining with Gas chromatography–mass spectroscopy and Cellular metabolism-Seahorse analyses, Prof. XU Mingkai and his colleagues from the Institute of Applied Ecology, Chinese Academy of Sciences, first revealed that superantigen SEC2 and its mutant can promote fatty acid uptake and synthesis in CD8+ T cells through mTOR/PPARγ and mTOR/SREBP signaling pathways, respectively. Stimulated by superantigen, CD8+ T cells can use the obtained fatty acid β-oxidation as an energy source to maintain effector function.
Researcher also found that ST-4, a SEC2 mutant with enhanced activity, could significantly increase the mitochondrial mass as well as mitochondrial membrane potential in CD8+ T cells. Seahorse analyses revealed that ST-4 could enhance the mitochondrial energy metabolism and ATP production in CD8+ T cells through p38-MAPK signaling pathway.
“The superantigen-directed fatty acid and mitochondrial energy metabolic programs are important for full activation and effector functions of CD8+ T cells in tumor immunotherapy.” said Prof XU.
This achievement further enriched the molecular mechanism of T-cell immune response activated by superantigen and provided a new theoretical insight for the clinical application of superantigen.
The study entitled "Staphylococcal enterotoxin C2 mutant–directed fatty acid and mitochondrial energy metabolic programs regulate CD8+ T cell activation" has been published in Journal of Immunology, a journal owned and published by The American Association of Immunologists, Inc.
This study was funded by the Strategic Priority Research Program of the Chinese Academy of Sciences, the Liaoning Xingliao Talent Programme, and the Young and Middle-aged S&T Innovative Talent Programme of Shenyang Science and Technology Bureau.