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

Beixue Gao, Qingfei Kong, Kyeorda Kemp, Yuan Si Zhao, Deyu Fang*

*Corresponding author for this work

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

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 programto 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.

Original languageEnglish (US)
Pages (from-to)899-904
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number3
DOIs
StatePublished - Jan 17 2012

Keywords

  • FoxO3a sequestration
  • T-cell anergic gene

ASJC Scopus subject areas

  • General

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