Fig. 4

Tregs exhibit decreased glycolysis but increased FAO and OXPHOS in functional status. 1 The PI3K-Akt-mTOR-HIF-1α pathway negatively influences Treg function by promoting glycolysis at the cost of decreased OXPHOS and FAO, and this axis is inhibited by CTLA-4- and PD-1-stimulated Foxp3 expression. PTEN and AMPK are the upstream inhibitors of PI3K and mTORC1, respectively, promoting Treg functional stability. HIF-2α relieves the suppression of HIF-1α on Treg function. 2 Tregs show high mitochondrial mass and excessive ROS production, which promotes Foxp3 expression by activating the binding of NFAT on the CNS2 enhancer of Foxp3. Additionally, Tfam and the mitochondrial respiratory chain are essential for the maintenance of Treg suppressive capacity. 3 The increased FAO is stimulated by the high expression of AMPK. FAS, especially the mevalonate pathway, which is activated by raptor/mTORC1 signaling and LKB1, influences Treg function. 4 Amino acids, especially arginine and leucine, drive effector Treg function. Synthesized by the enzyme Gclc in the presence of glutamine, glycine, and cysteine, GSH enhances Foxp3 expression and stimulates Treg suppressive capacity by suppressing serine. PTEN phosphatase and tensin homolog, ROS reactive oxygen species, NFAT nuclear factor of activated T cells, CNS2 conserved noncoding sequences 2, Tfam transcription factor A, FAS fatty acid synthesis, Gclc glutamate cysteine ligase, GSH glutathione