Dendritic cell SIRT1-HIF1α axis programs the differentiation of CD4+ T cells through IL-12 and TGF-β1
Dendritic cell SIRT1-HIF1α axis programs the differentiation of CD4+ T cells through IL-12 and TGF-β1
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DOI：
10.1073/pnas.1420419112
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发表时间：
2015-03-03
影响因子：
11.1
通讯作者：
Yang, Ruifu
中科院分区：
文献类型：
--
作者：
Liu, Guangwei;Bi, Yujing;Yang, Ruifu
幼稚CD4(+) T细胞分化成不同的谱系在介导适应性免疫或维持免疫耐受中发挥着关键作用。除了作为第一道防线外，先天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。在这里，我们发现sirtuin 1 (SIRT1)，一种III型组蛋白脱乙酰酶，在介导树突状细胞(DC)促炎信号转导中发挥着重要作用，从而调节促炎T辅助1型(T(H)1)细胞和抗炎Foxp3(+)调节性T细胞(T-reg细胞)的平衡。 DC 中 SIRT1 的基因缺失抑制了 T-reg 细胞的产生，同时驱动 T(H)1 发育，从而增强了 T 细胞介导的针对微生物反应的炎症。除此之外，SIRT1 通过缺氧诱导因子 1 α (HIF1 α) 依赖性途径发出信号，通过 DC 衍生的 IL-12 和 TGF-β 1 协调相互的 T(H)1 和 Treg 谱系承诺。我们的研究表明基于 DC 的 SIRT1-HIF1 α 代谢检查点在控制 T 细胞谱系规范中。
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 (T(H)1) cells and anti-inflammatory Foxp3(+) regulatory T cells (T-reg cells). Genetic deletion of SIRT1 in DCs restrained the generation of T-reg cells while driving T(H)1 development, resulting in an enhanced T-cell-mediated inflammation against microbial responses. Beyond this finding, SIRT1 signaled through a hypoxia-inducible factor-1 alpha (HIF1 alpha)-dependent pathway, orchestrating the reciprocal T(H)1 and Treg lineage commitment through DC-derived IL-12 and TGF-beta 1. Our studies implicates a DC-based SIRT1-HIF1 alpha metabolic checkpoint in controlling T-cell lineage specification.