αKG inhibits Regulatory T cell differentiation by coupling lipidome remodelling to mitochondrial metabolism

The differentiation of CD4 T cells to a specific effector fate is metabolically regulated, integrating glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) with transcriptional and epigenetic changes. OXPHOS is tightly coordinated with the tricarboxylic acid (TCA) cycle but the precise role of TCA intermediates in CD4 T cell differentiation remain unclear. Here we demonstrate that α-ketoglutarate (α-KG) inhibited regulatory T cell (Treg) generation while conversely, increasing Th1 polarization. In accord with these data, α-KG promoted the effector profile of Treg-polarized chimeric antigen receptor-engineered T cells against the ErbB2 tumor antigen. Mechanistically, α-KG significantly altered transcripts of genes involved in lipid-related processes, inducing a robust lipidome-wide remodelling and decreased membrane fluidity. A massive increase in storage and mitochondria lipids was associated with expression of mitochondrial genes and a significantly augmented OXPHOS. Notably, inhibition of succinate dehydrogenase activity, the bridge between the TCA cycle and the electron transport chain, enforced Treg generation. Thus, our study identifies novel connections between α-KG, lipidome remodelling and OXPHOS in CD4 T cell fate decisions.