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Lkb1 orchestrates γδ T-cell metabolic and functional fitness to control IL-17-mediated autoimmune hepatitis

Cellular & Molecular Immunology (2024)Cite this article

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Abstract

γδ T cells play a crucial role in immune surveillance and serve as a bridge between innate and adaptive immunity. However, the metabolic requirements and regulation of γδ T-cell development and function remain poorly understood. In this study, we investigated the role of liver kinase B1 (Lkb1), a serine/threonine kinase that links cellular metabolism with cell growth and proliferation, in γδ T-cell biology. Our findings demonstrate that Lkb1 is not only involved in regulating γδ T lineage commitment but also plays a critical role in γδ T-cell effector function. Specifically, T-cell-specific deletion of Lkb1 resulted in impaired thymocyte development and distinct alterations in γδ T-cell subsets in both the thymus and peripheral lymphoid tissues. Notably, loss of Lkb1 inhibited the commitment of Vγ1 and Vγ4 γδ T cells, promoted the maturation of IL-17-producing Vγ6 γδ T cells, and led to the occurrence of fatal autoimmune hepatitis (AIH). Notably, clearance of γδ T cells or blockade of IL-17 significantly attenuated AIH. Mechanistically, Lkb1 deficiency disrupted metabolic homeostasis and AMPK activity, accompanied by increased mTORC1 activation, thereby causing overactivation of γδ T cells and enhanced apoptosis. Interestingly, activation of AMPK or suppression of mTORC1 signaling effectively inhibited IL-17 levels and attenuated AIH in Lkb1-deficient mice. Our findings highlight the pivotal role of Lkb1 in maintaining the homeostasis of γδ T cells and preventing IL-17-mediated autoimmune diseases, providing new insights into the metabolic programs governing the subset determination and functional differentiation of thymic γδ T cells.

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Acknowledgements

The research reported in this publication was supported by the Natural Science Foundation of China (to M.Y., 82271754 and 82071737; to Z.Y., 32030036; to Q.Y., 32000615; and to P.F., 82301974), the China Postdoctoral Science Foundation (to P.F., 2023M741377), the Guangdong Basic and Applied Basic Research Fund (to Q.Y., 2023A1515012582; to P.F., 2022A1515110217; and to G.C., 2023B1515020018), and the 111 Project (to Z.Y., B16021). We would like to acknowledge Prof. Dr. Xun Sun from China Medical University for generously providing us with anti-TCR-Vγ6 (1C10-1F7) antibodies.

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  1. These authors contributed equally: Zhiqiang Xiao, Shanshan Wang, Liang Luo, Wenkai Lv.

Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People’s Hospital Affiliated with Jinan University, Jinan University, Zhuhai, 519000, China

    Zhiqiang Xiao, Quanli Yang, Guangchao Cao, Zhinan Yin & Meixiang Yang

  2. The Biomedical Translational Research Institute, School of Medicine, Jinan University, Guangzhou, 510632, China

    Zhiqiang Xiao, Shanshan Wang, Liang Luo, Wenkai Lv, Yadong Sun, Guangchao Cao, Zhinan Yin & Meixiang Yang

  3. Guangdong Provincial Key Laboratory of Spine and Spinal Cord Reconstruction, The Fifth Affiliated Hospital (Heyuan Shenhe People’s Hospital), Jinan University, Heyuan, 517000, China

    Peiran Feng & Meixiang Yang

  4. Key Laboratory of Ministry of Education for Viral Pathogenesis & Infection Prevention and Control (Jinan University). Guangzhou Key Laboratory for Germ-Free Animals and Microbiota Application. Institute of Laboratory Animal Science, School of Medicine, Jinan University, Guangzhou, 510632, China

    Jun He & Meixiang Yang

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Contributions

Conceptualization: M.Y. and Z.Y.; Methodology: Z.X., W.L., S.W., L.L., P.F., Y.S., and J.H.; Visualization: P.F. and Z.X.; Funding acquisition: M.Y.; Project administration: M.Y. and Z.Y.; Supervision: M.Y.; Writing draft: M.Y., Z.X., L.L., and G.C.

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Correspondence to Zhinan Yin or Meixiang Yang.

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The authors declare no competing interests. Z.Y. is an editorial board member of Cellular & Molecular Immunology, but he has not been involved in the peer review or the decision-making of the article.

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Xiao, Z., Wang, S., Luo, L. et al. Lkb1 orchestrates γδ T-cell metabolic and functional fitness to control IL-17-mediated autoimmune hepatitis. Cell Mol Immunol (2024). https://doi.org/10.1038/s41423-024-01163-9

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