The roles of Sirt1, a deacetylase, in immune tolerance and autoimmunity

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DESCRIPTION (provided by applicant): 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.