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Activation of Mevalonate Pathway Via LKB1 is Essential for Stability of Treg Cells

Timilshina, M;You, Z;Lacher, S;Acharya, S;Jiang, L;Kang, Y;Kim, J;Chang, H;Kim, K;Park, B;Song, J;Ko, H;Park, Y;Ma, M;Nepal, M;Jeong, T;Chung, Y;Waisman, A;Chang, J;

The function of Foxp3+ regulatory T cells (Treg cells) depends on lipid oxidation. However, the molecular mechanism by which Treg cells maintain lipid metabolism after activation remains elusive. LKB1 serine/threonine kinase acts as a coordinator of metabolism by linking cellular metabolism to the substrate AMP-activated protein kinase (AMPK). We found that mice with a conditional deletion of LKB1 in Treg cells developed a fatal autoimmune inflammation. LKB1-deficient Treg cells exhibited a reduced suppressive activity associated with effector T cell-like phenotypes. Mechanistically, LKB1 induced the activation of mevalonate pathway by up-regulating mevalonate genes in Treg cells independently of AMPK. LKB1-mediated mevalonate pathway was essential for Treg cell functional competency and stability by inducing Treg cell proliferation and by suppressing their IFN-γ and IL-17A expression. In agreement, mevalonate and its metabolite geranylgeranyl pyrophosphate (GGPP) not only inhibited the conversion of Treg cells to Th1- and Th17-like cells, but also enhanced the survival of LKB1-deficient Treg cells. Our results demonstrate that LKB1 is a key regulator of lipid metabolisms in Treg cells, involved in optimal programming of suppressive activity, immune homeostasis, and tolerance.