Molecular mechanisms of T cell anergy

描述(申请人提供)：T细胞的有效激活需要两个信号的整合：一个是抗原特异性的，由T细胞受体提供；第二个信号是通过共刺激受体的参与而激活的。无能是建立外周耐受的机制之一，是由T细胞通过其抗原受体不平衡地激活而没有同时参与共刺激受体而引起的。在这种情况下，T细胞不仅不会启动增殖反应，而且在存在共刺激的情况下，当用抗原重新刺激时，它们变得不能产生IL-2和增殖。与其他共刺激依赖的信号通路相比，无能刺激产生钙信号的优先激活。在这些条件下，NFAT转录因子家族的成员在缺少其主要转录伙伴AP-1的情况下被激活，指导无能反应的一组特定基因的表达。我们现在建议确定无能相关基因表达程序诱导的机制和后果。我们将解决的具体问题是：1)无能相关基因的表达是如何调节的？2)这些基因的激活会产生什么后果？3)无能相关基因的表达能够诱导T细胞耐受吗？为了实现这些目标，我们提出了三个具体的目标：1)研究在这些基因的启动子上发现的NFAT复合体的性质，将它们与那些与在生产性免疫反应中表达的基因相结合的基因区分开来；2)确定特定的无能相关基因在诱导T细胞耐受中的作用；以及3)在结构性激活无能相关基因表达的小鼠模型中，表征T细胞无能的诱导和维持及其在外周耐受中的作用。确定控制T细胞无能的转录程序激活的机制以及受这些基因表达影响的分子通路对于理解免疫耐受是如何建立的以及确定靶点将有助于设计新的治疗方法来治疗自身免疫性疾病、器官移植排斥和过敏。

DESCRIPTION (provided by applicant): Productive activation of T cells requires integration of two signals: one, antigen specific, provided by the T cell receptor; and a second signal activated by the engagement of co-stimulatory receptors. Anergy, one of the mechanisms that accounts for establishment of peripheral tolerance, is evoked by an unbalanced activation of T cells through their antigen receptor without simultaneous engagement of co-stimulatory receptors. In this situation, T cells not only do not start a proliferative response, but they become unable to produce IL-2 and proliferate when re-stimulated with antigen in the presence of co-stimulation. Anergic stimuli produce a preferential activation of calcium signaling relative to other co-stimulation dependent signaling pathways. Under these conditions, members of the NFAT family of transcription factors are activated in the absence of their main transcriptional copartner, AP-1, directing the expression of a specific set of genes characteristic of the anergic response. We now propose to determine the mechanisms and consequences of the induction of anergy-associated programs of gene expression. The specific questions we will address are: 1) How is the expression of anergy-associated genes regulated? 2) What are the consequences of the activation of those genes? 3) Is the expression of anergy-associated genes able to induce T cell tolerance? To achieve these goals we propose three specific aims: 1) to study the nature of the NFAT complexes found on the promoters of those genes, differentiating them from those that bind to genes expressed during a productive immune response; 2) To determine the role of specific anergy-associated genes in the induction of T cell tolerance; and 3) to characterize the induction and maintenance of T cell anergy and its role in peripheral tolerance in a mouse model that constitutively activates the expression of anergy-associated genes. Defining the mechanisms that control the activation of a transcriptional program specific of T cell anergy and the molecular pathways affected by the expression of those genes should prove valuable to understand how immune tolerance is established and to define targets that will help design new therapeutic approaches for autoimmune diseases, organ transplant rejection and allergy.