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

Abstract

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.

CLICK-chemoproteomics and molecular dynamics simulation reveals pregnenolone targets and their binding conformations in Th2 cells

“…Mitochondrial GLUD1, another P5 target, is known to play key role in replenishing tricarboxylic acid (TCA) cycle intermediate a-ketoglutarate from L-glutamate (48). a-Ketoglutarate performs crucial role in T-cell differentiation (49). Furthermore, GLUD1 enzyme plays an important role in insulin balance (50) and is one of the top candidates that is involved in long term memory and spatial learning (51).…”

The role of tumor metabolism in modulating T-Cell activity and in optimizing immunotherapy

“…Supplying a-ketoglutarate altered the methylation pattern of naïve CD4+ T cells activated under T reg polarizing conditions, which led to reduced T reg differentiation and decreased FOXP3 expression among adoptively transferred cells. These investigators suggested that a-ketoglutarate reprograms T cells to increase mitochondrial metabolism, which may affect the fate of CD4+ T-cell (specifically, T reg ) differentiation (212). Further research into the intersection of DNA methylation patterns and Tcell metabolism is warranted to inform a stronger mechanistic understanding of how this intersection can be therapeutically harnessed..…”