The roles of Synoviolin in immune tolerance and autoimmunity

描述(申请人提供)：T细胞耐受性受损是所有类型的自身免疫性疾病的原因，超过2300万美国人患有这种疾病。自从弗兰克·麦克法兰·伯内特爵士在20世纪50年代末首次描述免疫耐受并获得1960年诺贝尔生理学或医学奖以来，人们做出了巨大努力来确定与T细胞耐受有关的基因，尤其是外周T细胞耐受的分子机制仍然是免疫学上的一个谜。目前的学说是，在没有CD28共刺激的情况下，自身反应性T细胞上的TCR在识别自身抗原时，介导NFAT的激活，以促进抑制自身反应性T细胞激活的基因(称为无能基因)的表达。然而，更多的因素尚未确定，以完全解释T细胞耐受的分子谜团。我们推测，除了上调抑制基因外，无能信号还可能下调T细胞的某些激活物(正调节因子)，从而诱导和维持外周耐受。通过比较无能T细胞与单纯T细胞和活化T细胞的基因表达谱，我们证实了SynoViolin表达下调导致T细胞耐受。然后我们产生了T细胞特异性的SynoViin基因敲除小鼠。利用这一独特的小鼠模型，我们证明了Synovilin基因的缺失促进了T细胞耐受的诱导，抑制了T细胞的激活，并保护了小鼠免受自身免疫性疾病的影响，这意味着Synovilin是治疗自身免疫性疾病的潜在靶点。本研究旨在阐明聚维菌素诱导T细胞耐受和活化的分子机制。我们还将使用遗传学和药理学方法来评估Synoviin抑制在小鼠自身免疫治疗中的效果。

DESCRIPTION (provided by applicant): Impaired T cell tolerance is the cause of all types of autoimmune diseases, which suffers more than 23 million Americans. Since Sir Frank Macfarlane Burnet first described immune tolerance in late 1950s and received the 1960 Nobel Prize in Physiology or Medicine, tremendous efforts have identified genes that are responsible for T cell tolerance, the molecular mechanisms in particularly underlying the peripheral T cell tolerance remain an immunological mystery. The current dogma is that TCRs on self-reactive T cells, upon recognition of self-antigens without CD28 co-stimulation, mediate the activation of NFAT to promote the expression of genes that suppress the activation of self-reactive T cells (known as anergic genes). However, additional factors yet to be identified to fully explain the molecular puzzles of T cell tolerance. We speculate that, in addition to upregulating the suppressive genes, anergic signaling may down-regulate certain activators (positive regulators) of T cells to induce and maintain the peripheral tolerance. By comparing the gene expression profiles of anergic T cells with na?ve and activated T cells, we demonstrated that downregulation of Synoviolin expression leads to T cell tolerance. We then generated T cell-specific Synoviolin knockout mice. Using this unique mouse model, we demonstrated that genetic deletion of Synoviolin gene promotes T cell tolerance induction, inhibits T cell activation and protects mice from autoimmune disease, implying Synoviolin as a potential therapeutic target for autoimmune diseases. The current study is to illuminate the molecular mechanisms of Synoviolin in T cell tolerance and activation. We will also use both the genetic and pharmacological approaches to evaluate the efficacy of Synoviolin suppression in autoimmune treatment in mice.