期刊
CELL REPORTS
卷 27, 期 10, 页码 2948-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2019.05.020
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资金
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Science, ICT & Future Planning of the Korea government (MSIP) [2015R1C1A1A02036328, NRF-2014S1A2A2027903, NRF-2014R1A4A1071040]
- Deutsch Forschungsgemeinschaft (DFG) [CRC/TR 128, CRC/TR 156]
- National Research Foundation of Korea [2015R1C1A1A02036328] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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 up-regulating 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.
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