Molecular mechanisms of T cell anergy

描述（由申请人提供）：T细胞的生产激活需要整合两个信号：一个，抗原特异性，由T细胞受体提供；第二种信号是由共刺激受体激活的。能量是外周耐受性建立的机制之一，它是由T细胞通过其抗原受体的不平衡激活而引起的，而没有同时参与共刺激受体。在这种情况下，T细胞不仅不开始增殖反应，而且当它们在共同刺激的情况下再次受到抗原刺激时，它们变得无法产生IL-2并增殖。无能刺激产生钙信号的优先激活相对于其他共同刺激依赖的信号通路。在这种情况下，NFAT转录因子家族的成员在其主要转录伙伴AP-1缺失的情况下被激活，指导一组特定基因的表达，这些基因具有无能反应的特征。我们现在建议确定诱导能量相关的基因表达程序的机制和后果。我们将解决的具体问题是：1)能量相关基因的表达是如何调控的？2)激活这些基因的后果是什么？3)能量相关基因的表达是否能够诱导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)研究在这些基因启动子上发现的NFAT复合物的性质，将它们与在生产性免疫反应中表达的基因结合的NFAT复合物区分开来；2)确定特异性能相关基因在诱导T细胞耐受中的作用；3)在组成性激活能量相关基因表达的小鼠模型中，表征T细胞能量的诱导和维持及其在外周耐受性中的作用。确定控制T细胞能量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，以及确定靶标将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，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.