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Analysis of sirtuin 1 expression reveals a molecular explanation of IL-2–mediated reversal of T-cell tolerance

Gao, Beixue, Kong, Qingfei, Kemp, Kyeorda, Zhao, Yuan-Si, Fang, Deyu
Proceedings of the National Academy of Sciences of the United States of America 2012 v.109 no.3 pp. 899-904
T-lymphocytes, cytoplasm, gene expression, gene expression regulation, genes, histone deacetylase, immune response, interleukin-2, messenger RNA, transcription (genetics), transcription factors
The type III histone deacetylase sirtuin 1 (Sirt1) is a suppressor of both innate and adoptive immune responses. We have recently found that Sirt1 expression is highly induced in anergic T cells. However, the transcriptional program to regulate Sirt1 expression in T cells remains uncharacterized. Here we report that the early responsive genes 2 and 3, which can be up-regulated by T-cell receptor-mediated activation of nuclear factor of activated T-cell transcription factors and are involved in peripheral T-cell tolerance, bind to the sirt1 promoter to transcript sirt1 mRNA. In addition, the forkhead transcription factor, FoxO3a, interacts with early responsive genes 2/3 on the sirt1 promoter to synergistically regulate Sirt1 expression. Interestingly, IL-2, a cytokine that can reverse T-cell anergy, suppresses sirt1 transcription by sequestering FoxO3a to the cytoplasm through activating the PI3K-AKT pathway. Expression of the constitutively active form of FoxO3a blocks IL-2–mediated reversal of T-cell tolerance by retaining sirt1 expression. Our findings here provide a molecular explanation of IL-2–mediated reversion of T-cell anergy.