Analysis of sirtuin 1 expression reveals a molecular explanation of IL-2-mediated reversal of T-cell tolerance.
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.
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Beixue
B
Gao
Qingfei
Q
Kong
Kyeorda
K
Kemp
Yuan-Si
YS
Zhao
Deyu
D
Fang
D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D051767:Early Growth Response Protein 2 / Q000378:metabolism; D051776:Early Growth Response Protein 3 / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007108:Immune Tolerance / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D018448:Models, Immunological; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014158:Transcription, Genetic / Q000187:drug effects
D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; C497369:Egr3 protein, mouse; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D007376:Interleukin-2; D051776:Early Growth Response Protein 3; D056564:Sirtuin 1