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Dendritic cell SIRT1-HIF1? axis programs the differentiation of CD4+ T cells through IL-12 and TGF-?1.

ABSTRACT: 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 (HIF1?)-dependent pathway, orchestrating the reciprocal TH1 and T(reg) lineage commitment through DC-derived IL-12 and TGF-?1. Our studies implicates a DC-based SIRT1-HIF1? metabolic checkpoint in controlling T-cell lineage specification.

SUBMITTER: Liu G 

PROVIDER: S-EPMC4352801 | biostudies-other | 2015 Mar

REPOSITORIES: biostudies-other

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Dendritic cell SIRT1-HIF1α axis programs the differentiation of CD4+ T cells through IL-12 and TGF-β1.

Liu Guangwei G   Bi Yujing Y   Xue Lixiang L   Zhang Yan Y   Yang Hui H   Chen Xi X   Lu Yun Y   Zhang Zhengguo Z   Liu Huanrong H   Wang Xiao X   Wang Ruoning R   Chu Yiwei Y   Yang Ruifu R  

Proceedings of the National Academy of Sciences of the United States of America 20150217 9

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), conse  ...[more]

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