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.
Timilshina, Maheshwor and You, Zhiwei and Lacher, Sonja M. and Acharya, Suman and Jiang, Liyuan and Kang, Youra and Kim, Jung-Ae and Chang, Hyeun Wook and Kim, Keuk-Jun and Park, Byoungduck and Song, Jae-Hyoung and Ko, Hyun-Jeong and Park, Yun-Yong and Ma, Min-Jung and Nepal, Mahesh Raj and Jeong, Tae Cheon and Chung, Yeonseok and Waisman, Ari and Chang, Jae-Hoon, Activation of Mevalonate Pathway Via LKB1 is Essential for Stability of Treg Cells (January 9, 2019). Available at SSRN: https://ssrn.com/abstract=3312731 or http://dx.doi.org/10.2139/ssrn.3312731
This version of the paper has not been formally peer reviewed.
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