PDF(Pubmed)
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.
摘要：
γδT细胞在免疫监视中起着至关重要的作用，并且是先天免疫和适应性免疫之间的桥梁。然而,γδT细胞发育和功能的代谢需求和调节仍然知之甚少。在这项研究中,我们研究了肝激酶B1（Lkb1）的作用，丝氨酸/苏氨酸激酶，将细胞代谢与细胞生长和增殖联系起来，在γδT细胞生物学中。我们的发现表明，Lkb1不仅参与调节γδT谱系承诺，而且在γδT细胞效应子功能中起关键作用。具体来说,Lkb1的T细胞特异性缺失导致胸腺细胞发育受损，胸腺和外周淋巴组织中γδT细胞亚群发生明显变化。值得注意的是,Lkb1的缺失抑制了Vγ1和Vγ4γδT细胞的表达，促进产生IL-17的Vγ6γδT细胞的成熟，并导致致命的自身免疫性肝炎（AIH）的发生。值得注意的是,清除γδT细胞或阻断IL-17可显着减弱AIH。机械上,Lkb1缺乏破坏了代谢稳态和AMPK活性，伴随着mTORC1激活的增加，从而引起γδT细胞的过度活化并增强凋亡。有趣的是,在Lkb1缺陷小鼠中,AMPK的激活或mTORC1信号传导的抑制可有效抑制IL-17水平并减弱AIH.我们的发现强调了Lkb1在维持γδT细胞稳态和预防IL-17介导的自身免疫性疾病中的关键作用。为控制胸腺γδT细胞亚群确定和功能分化的代谢程序提供新的见解。
