Activation of Mevalonate Pathway via LKB1 Is Essential for Stability of T_reg Cells

The function of regulatory T (T_reg) cells depends on lipid oxidation. However, the molecular mechanism by which T_reg cells maintain lipid metabolism after activation remains elusive. Liver kinase B1 (LKB1) acts as a coordinator by linking cellular metabolism to substrate AMP-activated protein kinase (AMPK). We show that deletion of LKB1 in T_reg cells exhibited reduced suppressive activity and developed fatal autoimmune inflammation. Mechanistically, LKB1 induced activation of the mevalonate pathway by upregulating mevalonate genes, which was essential for T_reg cell functional competency and stability by inducing T_reg cell proliferation and suppressing interferon-gamma and interleukin-17A expression independently of AMPK. Furthermore, LKB1 was found to regulate intracellular cholesterol homeostasis and to promote the mevalonate pathway. In agreement, mevalonate and its metabolite geranylgeranyl pyrophosphate inhibited conversion of T_reg cells and enhanced survival of LKB1-deficient T_reg mice. Thus, LKB1 is a key regulator of lipid metabolism in T_reg cells, involved in optimal programming of suppressive activity, immune homeostasis, and tolerance.