LKB1-PTEN axis controls Th1 and Th17 cell differentiation via regulating mTORC1

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 T-reg 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)1 alpha-mediated glycolysis. Inhibition of glycolysis or biallelic disruption of LKB1 and HIF1 alpha 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 center dot LKB1 maintains T cell homeostasis in a cell intrinsic manner. center dot Glycolysis is involved in the LKB1-mediated T cell differentiation. center dot LKB1 phosphorylates PTEN, not AMPK, to regulate mTORC1.

Automated summary

Deficiency of LKB1 in T cells leads to preferential differentiation into Th1 and Th17 cells in the absence of inflammation, mediated by glycolysis. LKB1 regulates mTORC1 activity by phosphorylating PTEN, controlling effector T cell differentiation in a T cell-intrinsic manner.