Figure 2.

Schematic diagram of energy‐generating regulators in Tregs. The mTORC1 and AMPK signaling pathways are major metabolic checkpoints that modulate the FoxP3 expression and immunosuppressive activity of Tregs. Upon TCR engagement and CD28 co‐stimulation, the PI3K/AKT pathway is activated and induces mTORC1 signaling. The mTORC1 pathway can also be stimulated by the sensing of growth factor (GF) or amino acid (AA) availability. mTORC1 activation represses FoxP3 expression and thus Treg function. FoxP3 inhibits MYC, a downstream target of mTORC1, and so exerts direct metabolic control. FoxP3 is also downregulated by HIF1α, which is activated either directly by hypoxia or via mTORC1. HIF1α is therefore also a modulator of Treg function. Indoleamine 2,3‐dioxygenase (IDO), an enzyme involved in tryptophan (Trp) catabolism, activates PTEN. PTEN opposes PI3K‐dependent mTOR activation and thus supports Treg function. mTORC1 negatively regulates AMPK, which is a major promotor of catabolism and also regulates FoxP3 expression. AMPK is activated when energy supplies become low (high AMP/ATP ratio). LKB1 drives both AMPK activity and the mevalonate pathway, which is critical for Treg metabolism and function. Activated AMPK can also signal via TSC1 to inhibit the mTORC1 pathway. Likewise, protein phosphatase 2A (PP2A) is a negative regulator of the mTORC1 pathway.