树突状细胞SIRT1-HIF1α轴通过白细胞介素-12和转化生长因子-β1调控CD4+ T细胞的分化。
Dendritic cell SIRT1-HIF1α axis programs the differentiation of CD4+ T cells through IL-12 and TGF-β1.
作者信息
Liu Guangwei, Bi Yujing, Xue Lixiang, Zhang Yan, Yang Hui, Chen Xi, Lu Yun, Zhang Zhengguo, Liu Huanrong, Wang Xiao, Wang Ruoning, Chu Yiwei, Yang Ruifu
机构信息
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Biotherapy Research Center and Institute of Immunobiology, Fudan University, Shanghai 200032, China;
State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;
出版信息
Proc Natl Acad Sci U S A. 2015 Mar 3;112(9):E957-65. doi: 10.1073/pnas.1420419112. Epub 2015 Feb 17.
The differentiation of naive CD4(+) T cells into distinct lineages plays critical roles in mediating adaptive immunity or maintaining immune tolerance. In addition to being a first line of defense, the innate immune system also actively instructs adaptive immunity through antigen presentation and immunoregulatory cytokine production. Here we found that sirtuin 1 (SIRT1), a type III histone deacetylase, plays an essential role in mediating proinflammatory signaling in dendritic cells (DCs), consequentially modulating the balance of proinflammatory T helper type 1 (TH1) cells and antiinflammatory Foxp3(+) regulatory T cells (T(reg) cells). Genetic deletion of SIRT1 in DCs restrained the generation of T(reg) cells while driving TH1 development, resulting in an enhanced T-cell-mediated inflammation against microbial responses. Beyond this finding, SIRT1 signaled through a hypoxia-inducible factor-1 alpha (HIF1α)-dependent pathway, orchestrating the reciprocal TH1 and T(reg) lineage commitment through DC-derived IL-12 and TGF-β1. Our studies implicates a DC-based SIRT1-HIF1α metabolic checkpoint in controlling T-cell lineage specification.
初始CD4(+) T细胞分化为不同谱系在介导适应性免疫或维持免疫耐受中起关键作用。除作为第一道防线外，固有免疫系统还通过抗原呈递和免疫调节细胞因子的产生积极指导适应性免疫。我们发现，Ⅲ型组蛋白去乙酰化酶沉默调节蛋白1（SIRT1）在介导树突状细胞（DC）的促炎信号传导中起重要作用，从而调节促炎性1型辅助性T细胞（TH1）和抗炎性叉头框蛋白3（Foxp3）(+)调节性T细胞（T(reg)细胞）之间的平衡。DC中SIRT1的基因缺失抑制了T(reg)细胞的产生，同时促进TH1的发育，导致T细胞介导的针对微生物反应的炎症增强。除此之外，SIRT1通过缺氧诱导因子-1α（HIF1α）依赖性途径发出信号，通过DC衍生的白细胞介素-12（IL-12）和转化生长因子-β1（TGF-β1）协调TH1和T(reg)谱系的相互定向分化。我们的研究表明，在控制T细胞谱系特化方面存在基于DC的SIRT1-HIF1α代谢检查点。
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