Alpha-ketoglutarate induces lipidome remodeling and mitochondrial metabolism to inhibit regulatory T cell differentiation

The differentiation of CD4 T cells is regulated by glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), integrating the cell's metabolism with transcriptional and epigenetic changes. However, the precise mechanisms coupling tricarboxylic (TCA) acid cycle intermediates to CD4 T cell differentiation remain unclear. Here we demonstrate that a-ketoglutarate (aKG) increased Th1 polarization while significantly inhibiting regulatory T cell (Treg) generation. Consistent with these data, aKG promoted the effector profile of Treg-polarized chimeric antigen receptor-engineered T cells against the ErbB2 tumor antigen. Mechanistically, aKG altered the transcription of >250 membrane-related genes, decreasing membrane fluidity and inducing a robust lipidome-wide remodelling. The massive increase in storage and mitochondria lipids was associated with 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 aKG, lipidome remodeling and OXPHOS in CD4 T cell fate decisions. Overall design: mRNA profiles of mouse naïve T cells, as well as T cells under Treg and Th polarizing conditions with and without alpha-ketoglutarate.