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

描述(申请人提供)：外周T细胞耐受性是抑制自身反应性T细胞的重要机制。这种耐受性的崩溃会导致自身免疫性疾病，如类风湿性关节炎。然而，T细胞耐受诱导和维持的分子机制在很大程度上仍不清楚。在初步研究中，我们发现Sirt1是一种III型脱乙酰酶，是调节T细胞活化和耐受的关键分子。在体外和小鼠体内，Sirt1的基因靶向突变导致T细胞活化和维持T细胞耐受性失败。结果，Sirt1-/-小鼠产生了自身反应抗体。有趣的是，Sirt1抑制AP-1家族转录因子的活性。此外，在T细胞耐受过程中，Sirt1的表达被高度诱导。先前的研究表明，AP-1的转录活性是T细胞激活所必需的，在耐受的T细胞中是受损的。因此，我们认为无能信号上调Sirt1的表达，上调的Sirt1抑制AP-1的转录激活，从而诱导T细胞耐受。Sirt1功能的丧失会导致T细胞耐受性的崩溃，Sirt1-/-小鼠可能会患上胶原性关节炎(CIA)。在这项应用中，我们建议确定Sirt1如何抑制T细胞激活，以及Sirt1如何通过靶向AP-1转录因子来诱导/维持T细胞外周耐受。此外，我们还将研究Sirt1缺乏对CIA发展的影响。拟议中的研究结果可能会揭示T细胞激活和耐受的一种新的调节机制。这项研究还可能通过调节Sirt1/AP-1的串扰，为开发抗自身免疫的方法提供有用的信息。 公共卫生相关性：这项工作的结果可能揭示T细胞激活和耐受的一种新的调节机制。这项研究还可能通过调节Sirt1/AP-1的串扰，为开发抗自身免疫的方法提供有用的信息。

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.