The proliferation and differentiation of T lymphocytes is regulated by antigen and cytokine signals but the induction of metabolic pathways is also required, resulting in an integration of environmental cues in cell fate decisions. Indeed, T lymphocyte activation is regulated by the metabolism of glucose, fatty acids and amino acids, allowing the cell to meet increased energetic and biosynthetic demands. Notably, we recently found that glutamine availability is a key determinant of T cell differentiation; CD4 lymphocytes undergo differentiation to IFNg-secreting Th1 effectors under conditions of optimal glutaminolysis but are converted to Foxp3+ regulatory T cells when glutamine catabolism is abrogated. We now show that the glutamine-derived metabolite, a-ketoglutarate (aKG), significantly augments IFNg-secretion while attenuating Treg generation. Our data indicate that aKG alters the epigenetic profile of naïve CD4 T cells activated under Treg polarizing conditions, markedly attenuating Foxp3+ Treg differentiation and increasing inflammatory cytokine expression. Adoptive transfer of these T cells into tumor-bearing mice results in enhanced tumor infiltration, decreased Foxp3 expression, and delayed tumor growth. Mechanistically, aKG leads to an energetic state that is reprogrammed towards a mitochondrial metabolism, with increased oxidative phosphorylation and a lipidome-wide remodeling. Notably, inhibition of triacylglyceride synthesis restores Treg differentiation, decreasing inflammatory gene expression. Thus, our study unravels a novel crosstalk between aKG, mitochondrial metabolism and triacylglyceride synthesis in controlling Treg fate.
Invitée par Emmanuel Donnadieu
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