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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI079056-03S1
Application #
8147894
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Peyman, John A
Project Start
2010-09-29
Project End
2011-09-28
Budget Start
2010-09-29
Budget End
2011-09-28
Support Year
3
Fiscal Year
2010
Total Cost
$180,030
Indirect Cost
Name
Northwestern University at Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Melo-Cardenas, Johanna; Xu, Yuanming; Wei, Juncheng et al. (2018) USP22 deficiency leads to myeloid leukemia upon oncogenic Kras activation through a PU.1-dependent mechanism. Blood 132:423-434
Wang, Wenhui; Li, Fei; Xu, Yuanming et al. (2018) JAK1-mediated Sirt1 phosphorylation functions as a negative feedback of the JAK1-STAT3 pathway. J Biol Chem 293:11067-11075
Yang, Yi; Kong, Sinyi; Zhang, Yana et al. (2018) The endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls a critical checkpoint in B cell development in mice. J Biol Chem 293:12934-12944
Wei, Juncheng; Chen, Lu; Li, Fei et al. (2018) HRD1-ERAD controls production of the hepatokine FGF21 through CREBH polyubiquitination. EMBO J 37:
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
Gao, Beixue; Kong, Qingfei; Zhang, Yana et al. (2017) The Histone Acetyltransferase Gcn5 Positively Regulates T Cell Activation. J Immunol 198:3927-3938
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; MascariƱas, 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

Showing the most recent 10 out of 40 publications