Mevalonate Metabolism fuels pro-inflammatory function of Vd2 T cells

Mevalonate metabolism is essential for proper functioning of eukaryotic cells. Widely prescribed drugs, like statins and bisphosphonates, inhibit specific enzymes in the mevalonate pathway and modulate immune responses. Intermediate metabolites of the pathway activate innate-like Vd2 T cells, while bisphosphonates effectively expand these cells for potential therapeutic use. Yet, the role of the mevalonate metabolism in Vd2 T cells is poorly defined. We show that in vitro and in vivo inhibition of the mevalonate metabolism results in compromised cytokine production and cytotoxic activity of Vd2 T cells. Impaired Vd2 T cell function is accompanied by global transcriptome changes. Protein prenylation and kinome analysis unraveled dysregulated signaling pathways as the leading cause of the reduced effector function of Vd2 T cells upon mevalonate pathway inhibition. Our findings reveal the importance of mevalonate metabolism for the proper functioning of Vd2 T cells and provides important considerations for improving their therapeutic use.EGA study EGAS00001007530