Peripheral T-cell tolerance is an important mechanism in suppressing self-reactive T cells. A breakdown of this tolerance causes autoimmune diseases such as rheumatoid arthritis. The molecular mechanisms underlying how T-cell tolerance is induced and is maintained, however, remain largely undefined. In the preliminary studies, we have found that Sirt1, a type III deacetylase, is a critical molecule in regulating the activation and the tolerance of T cells. Gene targeted mutation of Sirt1 in mice resulted in dramatically increased T-cells activation and failures in maintaining T-cell tolerance both in vitro and in mice. As a consequence, Sirt1-/- mice produce autoreactive antibodies. Interestingly, Sirt1 inhibits the activities of AP-1 family transcription factors. In addition, the expression of Sirt1 is highly induced during T-cell tolerization. Previous studies have demonstrated that AP-1 transcriptional activity is required for T-cell activation and is impaired in tolerized T cells. Therefore, we propose that anergic signaling upregulates Sirt1 expression, upregulated Sirt1 suppresses AP-1 transcriptional activation to induce T-cell tolerance. Loss of Sirt1 functions causes a breakdown of T-cell tolerance and Sirt1-/- mice may develop collagen-induced arthritis (CIA). In this application we propose to determine how Sirt1 suppresses T-cell activation and how Sirt1 induces/maintains T-cell periphery tolerance by targeting AP-1 transcription factors. Also, we will examine the effects of Sirt1-deficiency on the development of CIA. Results from the proposed research will potentially uncover a novel regulatory mechanism in T-cell activation and tolerance. This study will also likely generate useful information in the development of approaches against autoimmunity by modulating Sirt1/AP-1 cross-talk.
Results from this work will potentially uncover a novel regulatory mechanism in T cell activation and tolerance. This study will likely also generate useful information in the development of approaches against autoimmunity by modulating Sirt1/AP-1 cross talk.
|Gao, Beixue; Kong, Qingfei; Zhang, Yana et al. (2017) The Histone Acetyltransferase Gcn5 Positively Regulates T Cell Activation. J Immunol 198:3927-3938|
|Hou, Xia; Yang, Zhao; Zhang, Kezhong et al. (2017) SUMOylation represses the transcriptional activity of the Unfolded Protein Response transducer ATF6. Biochem Biophys Res Commun 494:446-451|
|Wang, Yajun; Yun, Chawon; Gao, Beixue et al. (2017) The Lysine Acetyltransferase GCN5 Is Required for iNKT Cell Development through EGR2 Acetylation. Cell Rep 20:600-612|
|Kong, Sinyi; Yang, Yi; Xu, Yuanming et al. (2016) Endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls B-cell immunity through degradation of the death receptor CD95/Fas. Proc Natl Acad Sci U S A 113:10394-9|
|Principe, Daniel R; DeCant, Brian; Mascariñas, Emman et al. (2016) TGF? Signaling in the Pancreatic Tumor Microenvironment Promotes Fibrosis and Immune Evasion to Facilitate Tumorigenesis. Cancer Res 76:2525-39|
|Haque, Mohammad; Song, Jianyong; Fino, Kristin et al. (2016) Stem cell-derived tissue-associated regulatory T cells ameliorate the development of autoimmunity. Sci Rep 6:20588|
|Haque, Mohammad; Song, Jianyong; Fino, Kristin et al. (2016) C-Myc regulation by costimulatory signals modulates the generation of CD8+ memory T cells during viral infection. Open Biol 6:150208|
|Xu, Yuanming; Zhao, Fang; Qiu, Quan et al. (2016) The ER membrane-anchored ubiquitin ligase Hrd1 is a positive regulator of T-cell immunity. Nat Commun 7:12073|
|Huang, Qi-Quan; Perlman, Harris; Birkett, Robert et al. (2015) CD11c-mediated deletion of Flip promotes autoreactivity and inflammatory arthritis. Nat Commun 6:7086|
|Melo-Cardenas, Johanna; Kong, Sinyi; Fang, Deyu (2015) A Hrd way for MHC-II expression. Oncotarget 6:21767-8|
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