Staphylococcal Enterotoxin C2 Mutant-Directed Fatty Acid and Mitochondrial Energy Metabolic Programs Regulate CD8+ T Cell Activation.

Fu, Xuanhe; Xu, Mingkai; Zhang, Huiwen; Li, Yongqiang; Li, Yansheng; Zhang, Chenggang

CD8+ T cells can switch between fatty acid catabolism and mitochondrial energy metabolism to sustain expansion and their cytotoxic functions. ST-4 is a TCR-enhanced mutant derived from superantigen staphylococcal enterotoxin C2 (SEC2), which can hyperactivate CD4+ T cells without MHC class II molecules. However, whether ST-4/SEC2 can enhance metabolic reprogramming in CD8+ T cells remains poorly understood. In this study, we found that ST-4, but not SEC2, could induce proliferation of purified CD8+ T cell from BALB/c mice in Vβ8.2- and -8.3-specific manners. Results of gas chromatography-mass spectroscopy analysis showed that fatty acid contents in CD8+ T cells were increased after ST-4 stimulation. Flow cytometry and Seahorse analyses showed that ST-4 significantly promoted mitochondrial energy metabolism in CD8+ T cells. We also observed significantly upregulated levels of gene transcripts for fatty acid uptake and synthesis, and significantly increased protein expression levels of fatty acid and mitochondrial metabolic markers of mTOR/PPARγ/SREBP1 and p38-MAPK signaling pathways in ST-4-activated CD8+ T cells. However, blocking mTOR, PPARγ, SREBP1, or p38-MAPK signals with specific inhibitors could significantly relieve the enhanced fatty acid catabolism and mitochondrial capacity induced by ST-4. In addition, blocking these signals inhibited ST-4-stimulated CD8+ T cell proliferation and effector functions. Taken together, our findings demonstrate that ST-4 enhanced fatty acid and mitochondria metabolic reprogramming through mTOR/PPARγ/SREBP and p38-MAPK signaling pathways, which may be important regulatory mechanisms of CD8+ T cell activation. Understanding the effects of ST-4-induced regulatory metabolic networks on CD8+ T cells provide important mechanistic insights to superantigen-based tumor therapy.