Inhibitory co-receptor Lag3 supports Foxp3+ regulatory T cell function by restraining Myc-dependent metabolic programming

IF 25.5 1区 医学 Q1 IMMUNOLOGY Immunity Pub Date : 2024-09-04 DOI:10.1016/j.immuni.2024.08.008
Dongkyun Kim, Giha Kim, Rongzhen Yu, Juyeun Lee, Sohee Kim, Mia R. Gleason, Kevin Qiu, Elena Montauti, Li Lily Wang, Deyu Fang, Jaehyuk Choi, Navdeep S. Chandel, Samuel Weinberg, Booki Min
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Abstract

Lymphocyte activation gene 3 (Lag3) is an inhibitory co-receptor expressed on activated T cells and has been proposed to regulate regulatory T (Treg) cell function. However, its precise modality and mechanisms remain elusive. We generated Treg cell-specific Lag3-mutant mouse models and found that Lag3 was essential for Treg cell control of autoimmunity. RNA sequencing analysis revealed that Lag3 mutation altered genes associated with metabolic processes, especially Myc target genes. Myc expression in Lag3-mutant Treg cells was increased to the level seen in conventional T helper (Th)1-type effector cells and directly correlated with their metabolic profiles and in vivo suppressive functions. The phosphatidylinositol 3-kinase (PI3K)-Akt-Rictor pathway was activated in Lag3-mutant Treg cells, and inhibiting PI3K, Rictor, or lactate dehydrogenase A (Ldha), a key Myc target enzyme converting pyruvate to lactate, was sufficient to restore normal metabolism and suppressive function in Lag3-mutant Treg cells. These findings indicate that Lag3 supports Treg cell suppression partly by tuning Myc-dependent metabolic programming.

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抑制性共受体Lag3通过抑制依赖于Myc的代谢程序来支持Foxp3+调节性T细胞的功能
淋巴细胞活化基因 3(Lag3)是一种表达在活化 T 细胞上的抑制性共受体,被认为能调节调节性 T(Treg)细胞的功能。然而,其确切的模式和机制仍然难以捉摸。我们建立了Treg细胞特异性Lag3突变小鼠模型,发现Lag3对Treg细胞控制自身免疫至关重要。RNA测序分析显示,Lag3突变改变了与代谢过程相关的基因,尤其是Myc靶基因。在Lag3突变的Treg细胞中,Myc的表达增加到了传统T辅助细胞(Th)1型效应细胞的水平,并与其代谢特征和体内抑制功能直接相关。Lag3突变Treg细胞中的磷脂酰肌醇3-激酶(PI3K)-Akt-Rictor通路被激活,抑制PI3K、Rictor或乳酸脱氢酶A(Ldha)(一种将丙酮酸转化为乳酸的关键Myc靶酶)足以恢复Lag3突变Treg细胞的正常代谢和抑制功能。这些发现表明,Lag3 部分是通过调整依赖于 Myc 的代谢程序来支持 Treg 细胞的抑制作用。
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来源期刊
Immunity
Immunity 医学-免疫学
CiteScore
49.40
自引率
2.20%
发文量
205
审稿时长
6 months
期刊介绍: Immunity is a publication that focuses on publishing significant advancements in research related to immunology. We encourage the submission of studies that offer groundbreaking immunological discoveries, whether at the molecular, cellular, or whole organism level. Topics of interest encompass a wide range, such as cancer, infectious diseases, neuroimmunology, autoimmune diseases, allergies, mucosal immunity, metabolic diseases, and homeostasis.
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