ITK: an emerging target for treatment of T cell-mediated autoimmune disease

描述（由申请人提供）：ITK：治疗T细胞介导的自身免疫性疾病的新靶点。淋巴细胞介导的自身免疫性疾病是由自身耐受性的破坏引起的。抑制T细胞蛋白CTLA-4是调节自身耐受性的关键蛋白之一。当CTLA-4缺失时，小鼠会迅速死于一种致命的多器官自身免疫性疾病，并在三周龄时死亡。我们实验室最近的研究表明，CTLA-4在预防自身免疫方面有两种不同的功能。首先，FOXP3+调节性T细胞维持T细胞耐受性的功能需要CTLA-4。其次，常规T细胞需要CTLA-4来阻断非炎症条件下组织中异常激活的自反应性T细胞积累。目前尚不清楚共刺激分子如何控制异常激活的自反应性T细胞浸润和损伤组织。基于观察到Tec激酶Itk的零突变可以阻止活化的T细胞迁移和Ctla4-/-小鼠的自身免疫病理，我们提出Itk激活对于T细胞介导的自身免疫性疾病至关重要。我们假设ITK是协同激活VAV1和VAV1下游导致肌动蛋白聚合和细胞骨架重组的途径所必需的。此外，我们提出ITK通过磷酸化和激活Src家族激酶FYN来激活VAV1，而FYN反过来磷酸化和激活VAV1。我们将通过检查Itk-/-小鼠体内和体外自身反应性T细胞的迁移行为来验证这一假设，以确定Itk控制T细胞向非淋巴组织运动的分子机制。我们还将确定ITK是否通过激活FYN来调节原代T细胞中的细胞骨架重组，FYN是否是原代T细胞中肌动蛋白聚合和细胞骨架重组所必需的，并有助于自身免疫性疾病的进展。最后，我们将研究ITK小分子抑制剂抑制动物I型糖尿病的疗效和机制，开始探索靶向ITK阻断在临床治疗各种器官特异性自身免疫性疾病中的应用。

DESCRIPTION (provided by applicant): ITK: an emerging target for treatment of T cell-mediated autoimmune diseases Lymphocyte-mediated autoimmune diseases arise from a breakdown of self-tolerance. One of the key proteins regulating self-tolerance is the inhibitory T cell protein, CTLA-4. When CTLA-4 is absent, mice succumb to a rapid and fatal multi-organ autoimmune disease, and die by three weeks of age. Recent studies from our labs have demonstrated that CTLA-4 has two distinct functions in preventing autoimmunity. First, CTLA-4 is required for the function of FOXP3+ regulatory T cells in maintaining T cell tolerance. Second, CTLA-4 is required in conventional T cells, to block aberrantly activated self-reactive T cell accumulation in tissues under non-inflammatory conditions. It is unknown how costimulatory molecules control aberrantly activated self-reactive T cells from infiltrating and damaging tissues. Based on the observation that the null mutation of the Tec kinase Itk prevents activated T cell migration and autoimmune pathology of Ctla4-/- mice, we propose that ITK activation is critical for T cell-mediated autoimmune diseases. We hypothesize that ITK is required for the synergistic activation of VAV1 and the pathways downstream of VAV1 leading to actin polymerization and cytoskeletal reorganization. Further, we propose that ITK activates VAV1 by phosphorylating and activating the Src family kinase, FYN, which in turn phosphorylates and activates VAV1. We will test this hypothesis by examining the migratory behavior of self-reactive T cells from Itk-/- mice in vitro and in vivo to determine the molecular mechanism by which ITK controls T cell movement into non-lymphoid tissues. We will also determine whether ITK regulates cytoskeletal reorganization in primary T cells by activating FYN, whether FYN is required for actin polymerization and cytoskeletal reorganization in primary T cells and contribute to autoimmune disease progression. Finally, we will investigate the efficacy and mechanism of suppression of Type I diabetes in animals by small molecule inhibitors of ITK, to begin to explore the utility of targeted ITK blockade in clinics to treat various organ-specific autoimmune diseases.