美国西北大学Booki Min等研究人员合作发现，抑制性共受体Lag3通过限制Myc依赖的代谢程序来支持Foxp3⁺调节性T细胞的功能。该项研究成果于2024年9月4日在线发表在《免疫》杂志上。

研究人员生成了调节性T细胞（Treg）特异性的淋巴细胞活化基因3（Lag3）突变小鼠模型，发现Lag3在Treg细胞控制自身免疫中至关重要。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靶基因的表达。Lag3突变的Treg细胞中Myc表达增加，达到常规T辅助（Th）1型效应细胞的水平，并与其代谢特征及其在体内的抑制功能直接相关。

磷脂酰肌醇3-激酶（PI3K）-Akt-Rictor通路在Lag3突变的Treg细胞中被激活，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靶向酶）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通过调节Myc依赖的代谢程序来支持Treg细胞的抑制功能。

据了解，Lag3是活化T细胞上表达的抑制性共受体，已被提出可能调控调Treg的功能。然而，其具体机制仍不清楚。

附：英文原文

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

Author: 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

Issue&Volume: 2024-09-04

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.

DOI: 10.1016/j.immuni.2024.08.008

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00407-2