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Immuno-environmental change triggers CD4+ T cell differentiation. T cell specialization activates metabolic signal pathways to meet energy requirements. Defective T cell-intrinsic metabolism can aggravate immunopathology in chronic diseases. Liver kinase B1 (LKB1) deletion in T cell or Treg cell results in systemic inflammatory symptoms, indicating a crucial role of LKB1 in T cells. However, the mechanism underlying the development of inflammation is unclear. In our study, LKB1-deficient T cells were differentiated preferentially into Th1 and Th17 cells in the absence of inflammation. Mechanistically, LKB1 directly binds and phosphorylates phosphatase and tensin homolog (PTEN), an upstream regulator of mammalian target of rapamycin complex 1 (mTORC1), which is independent of AMP-activated protein kinase (AMPK). As a result, LKB1 deficiency was associated with increased mTORC1 activity and hypoxia-inducible factor (HIF)1α-mediated glycolysis. Inhibition of glycolysis or biallelic disruption of LKB1 and HIF1α abrogated this phenotype, suggesting Th1- and Th17-biased differentiation in LKB1-deficient T cells was mediated by glycolysis. Our study indicates that LKB1 controls mTORC1 signaling through PTEN activation, not AMPK, which controls effector T cell differentiation in a T cell-intrinsic manner. KEY MESSAGES: • LKB1 maintains T cell homeostasis in a cell intrinsic manner. • Glycolysis is involved in the LKB1-mediated T cell differentiation. • LKB1 phosphorylates PTEN, not AMPK, to regulate mTORC1.

Mevalonate is a precursor in a biosynthetic pathway that is important for the coordination of regulatory T cell (Treg) proliferation and upregulation of the suppressive function that establishes the functional competency of Tregs. The extensive role of mevalonate and its underlying effect on Treg differentiation are still unclear. We found that mevalonate increases in vitro differentiation of induced Tregs (iTregs) without broadly affecting Th1 and Th17 cell differentiation. Furthermore, an adoptive transfer study showed that mevalonate enhanced peripherally induced Treg cells (pTregs) in mesenteric lymphocytes in vivo. Mevalonate-treated iTregs exhibited greater suppressive activity against effector cells than untreated Tregs. Mechanistically, mevalonate enhanced transforming growth factor (TGF)-β signaling by increasing the phosphorylation of Smad3, but not Smad2, and by promoting Foxp3 expression. Furthermore, we demonstrated that mevalonate treatment ameliorated dextran sulfate sodium (DSS)-induced colitis and resulted in an increased percentage of Tregs in vivo. Our results suggest that mevalonate enhanced Treg differentiation and ameliorated DSS colitis, indicating its potential for treatment of inflammatory diseases.