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

作　　者：Zhiqiang Xiao Shanshan Wang Liang Luo Wenkai Lv Peiran Feng Yadong Sun Quanli Yang Jun He Guangchao Cao Zhinan Yin Meixiang Yang 

机构地区：[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

出　　处：《Cellular & Molecular Immunology》2024年第6期546-560,共15页中国免疫学杂志（英文版）

基　　金：Natural Science Foundation of China(to M.Y.,82271754 and 82071737,to Z.Y.,32030036,to Q.Y.,32000615,and to P.F.,82301974);China Postdoctoral Science Foundation(to P.F.,2023M741377);Guangdong Basic and Applied Basic Research Fund(to Q.Y.,2023A1515012582,to P.F.,2022A1515110217,and to G.C.,2023B1515020018);111 Project(to Z.Y.,B16021).

摘　　要：γδT cells play a crucial role in immune surveillance and serve as a bridge between innate and adaptive immunity.However,the metabolic requirements and regulation ofγδT-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,inγδT-cell biology.Our findings demonstrate that Lkb1 is not only involved in regulatingγδT lineage commitment but also plays a critical role inγδT-cell effector function.Specifically,T-cell-specific deletion of Lkb1 resulted in impaired thymocyte development and distinct alterations inγδT-cell subsets in both the thymus and peripheral lymphoid tissues.Notably,loss of Lkb1 inhibited the commitment of Vγ1 and Vγ4γδT cells,promoted the maturation of IL-17-producing Vγ6γδT cells,and led to the occurrence of fatal autoimmune hepatitis(AIH).Notably,clearance ofγδT 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 ofγδT 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 ofγδT cells and preventing IL-17-mediated autoimmune diseases,providing new insights into the metabolic programs governing the subset determination and functional differentiation of thymicγδT cells.

关 键 词：LKB1 γδT cell Autoimmune hepatitis IL-17 Metabolic quiescence 

分 类 号：R392[医药卫生—免疫学] R575[医药卫生—基础医学]