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Article Abstract
The function of regulatory T (T) cells depends on lipid oxidation. However, the molecular mechanism by which T 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 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 cell functional competency and stability by inducing T 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 cells and enhanced survival of LKB1-deficient T mice. Thus, LKB1 is a key regulator of lipid metabolism in T cells, involved in optimal programming of suppressive activity, immune homeostasis, and tolerance.
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| http://dx.doi.org/10.1016/j.celrep.2019.05.020 | DOI Listing |
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