Molecular mechanisms of T cell anergy

描述（由申请人提供）：T细胞的生产性活化需要两种信号的整合：一种是由T细胞受体提供的抗原特异性信号;另一种是由共刺激受体的参与激活的信号。无反应性是导致外周耐受建立的机制之一，其由T细胞通过其抗原受体的不平衡活化引起，而不同时接合共刺激受体。在这种情况下，T细胞不仅不开始增殖反应，而且当在共刺激存在下用抗原再刺激时，它们变得不能产生IL-2和增殖。相对于其他共刺激依赖性信号传导途径，无反应性刺激产生钙信号传导的优先激活。在这些条件下，转录因子的NFAT家族的成员在其主要转录配偶体AP-1不存在的情况下被激活，AP-1指导无反应性反应的特定基因组的表达。我们现在建议确定无能量相关基因表达程序的诱导机制和后果。我们将解决的具体问题是：1）无能量相关基因的表达是如何调节的？2)这些基因激活的后果是什么？3)无能量相关基因的表达能否诱导T细胞耐受？为了实现这些目标，我们提出了三个具体目标：1）研究在这些基因的启动子上发现的NFAT复合物的性质，将它们与在生产性免疫应答期间与表达的基因结合的那些NFAT复合物区分开来; 2）确定特定的无能量相关基因在诱导T细胞耐受中的作用;和3）在组成性激活无反应性相关基因表达的小鼠模型中表征T细胞无反应性的诱导和维持及其在外周耐受性中的作用。确定控制T细胞无能特异性转录程序激活的机制以及受这些基因表达影响的分子途径，对于理解免疫耐受是如何建立的，以及确定有助于设计自身免疫性疾病、器官移植排斥和过敏的新治疗方法的靶点，应该是有价值的。

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.