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

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Abstract

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.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by Yeungnam University Research Grant 220A380067 (http://www.yu.ac.kr/index.php). The funders had no role in the study design, data collection and analysis, decision to publish, or manuscript preparation.

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  1. College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea

    Mahesh Pandit, Maheshwor Timilshina & Jae-Hoon Chang

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  1. Mahesh Pandit
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  2. Maheshwor Timilshina
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Contributions

M.P. and M.T. collected, analyzed, and interpreted the data, and arranged the figure. J.H.C. and M.P. wrote the manuscript. J.H.C. conceptualized, designed, and supervised the study and obtained funding.

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Correspondence to Jae-Hoon Chang.

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All animal studies were reviewed and approved by the Institutional Animal Care and Use Committee of Yeungnam University (Approval numbers 2017-030, 2017-003, 2017-031, and 2014-018), and National Institute of Health Guidelines were followed to care for the animals and perform the experiments.

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The authors declare no competing interests.

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Pandit, M., Timilshina, M. & Chang, JH. LKB1-PTEN axis controls Th1 and Th17 cell differentiation via regulating mTORC1. J Mol Med 99, 1139–1150 (2021). https://doi.org/10.1007/s00109-021-02090-2

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  • DOI: https://doi.org/10.1007/s00109-021-02090-2

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