2. Academic Validation
  3. Lkb1 orchestrates γδ T-cell metabolic and functional fitness to control IL-17-mediated autoimmune hepatitis

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

  • Cell Mol Immunol. 2024 Apr 19. doi: 10.1038/s41423-024-01163-9.
Zhiqiang Xiao # 1 2,  Shanshan Wang # 2,  Liang Luo # 2,  Wenkai Lv # 2,  Peiran Feng 3,  Yadong Sun 2,  Quanli Yang 1,  Jun He 4,  Guangchao Cao 1 2,  Zhinan Yin 5 6,  Meixiang Yang 7 8 9 10
Affiliations

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.
  • 2 The Biomedical Translational Research Institute, School of Medicine, Jinan University, Guangzhou, 510632, China.
  • 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.
  • 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.
  • 5 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. tzhinan@jnu.edu.cn.
  • 6 The Biomedical Translational Research Institute, School of Medicine, Jinan University, Guangzhou, 510632, China. tzhinan@jnu.edu.cn.
  • 7 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. mxyang@jnu.edu.cn.
  • 8 The Biomedical Translational Research Institute, School of Medicine, Jinan University, Guangzhou, 510632, China. mxyang@jnu.edu.cn.
  • 9 Guangdong Provincial Key Laboratory of Spine and Spinal Cord Reconstruction, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, 517000, China. mxyang@jnu.edu.cn.
  • 10 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. mxyang@jnu.edu.cn.
  • # Contributed equally.
PMID: 38641698 DOI: 10.1038/s41423-024-01163-9
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.

Keywords

Autoimmune hepatitis; IL-17; Lkb1; Metabolic quiescence; γδ T cell.

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