Lymphocyte activation gene 3 (Lag3) supports Foxp3 + Treg cell function by restraining c-Myc-dependent aerobic glycolysis.
Lymphocyte activation gene 3 (Lag3) supports Foxp3 + Treg cell function by restraining c-Myc-dependent aerobic glycolysis.
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淋巴细胞激活基因 3 (Lag3) 通过抑制 c-Myc 依赖性有氧糖酵解来支持 Foxp3 Treg 细胞功能。
DOI：
10.1101/2023.02.13.528371
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Min,Booki
中科院分区：
文献类型：
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作者：
Kim,Dongkyun;Kim,Giha;Yu,Rongzhen;Lee,Juyeun;Kim,Sohee;Qiu,Kevin;Montauti,Elena;Fang,Deyu;Chandel,NavdeepS;Choi,Jaehyuk;Min,Booki
淋巴细胞活化基因3（Lag3）由于其抑制效应T细胞活性的能力而成为下一代免疫检查点分子。Foxp3+调节性T（Treg）细胞是免疫和耐受的主要调节者，也高度表达Lag3。虽然Lag3被认为是Treg细胞介导的免疫调节所必需的，但其确切作用和潜在机制在很大程度上仍然难以捉摸。在这项研究中，我们报告了Lag3是Treg细胞控制自身免疫性炎症所不可或缺的。利用新产生的Treg细胞特异性Lag3突变小鼠模型，我们发现这些动物对自身免疫性疾病高度易感，表明Treg细胞功能缺陷。全基因组转录组分析进一步揭示了Lag3突变Treg细胞上调参与代谢过程的基因。从机制上讲，我们发现Lag3限制了Treg细胞表达Myc，这是有氧糖酵解的关键调节因子。我们进一步发现，Lag3依赖性Myc表达决定了Treg细胞的代谢程序以及抑制自身免疫性炎症的体内功能。总之，我们的结果揭示了Lag3通过调节Myc依赖性代谢编程支持Treg细胞抑制功能的新功能。
Lymphocyte activation gene 3 (Lag3) has emerged as the next-generation immune checkpoint molecule due to its ability to inhibit effector T cell activity. Foxp3+regulatory T (Treg) cells, a master regulator of immunity and tolerance, also highly express Lag3. While Lag3 is thought to be necessary for Treg cell-mediated regulation of immunity, the precise roles and underlying mechanisms remain largely elusive. In this study, we report that Lag3 is indispensable for Treg cells to control autoimmune inflammation. Utilizing a newly generated Treg cell specific Lag3 mutant mouse model, we found that these animals are highly susceptible to autoimmune diseases, suggesting defective Treg cell function. Genome wide transcriptome analysis further uncovered that Lag3 mutant Treg cells upregulated genes involved in metabolic processes. Mechanistically, we found that Lag3 limits Treg cell expression of Myc, a key regulator of aerobic glycolysis. We further found that Lag3-dependent Myc expression determines Treg cells’ metabolic programming as well as the in vivo function to suppress autoimmune inflammation. Taken together, our results uncovered a novel function of Lag3 in supporting Treg cell suppressive function by regulating Myc-dependent metabolic programming.