FUNCTIONAL CHARACTERIZATION OF ANERGIC HELPER T CELLS

体内对外周自身抗原的免疫耐受取决于 几种机制的综合作用：克隆无能、缺失、 压制和克隆无知。每种机制都是抗原- 因此，对其基本性质的理解可以 作为设计合理的战略的基础 自身免疫性疾病的治疗。在此项目下，在 过去的研究主要集中在免疫反应性的调节上。 克隆性无能机制使用克隆的CD4+T细胞。我们的 实验表明克隆性无能不仅抑制T细胞的生长 通过阻断自分泌生长因子的分泌，也通过 阻断淋巴因子反应性的上调。克隆性 无能症被发现与阻止信号的缺陷有关 从到达MAP激活ERK和JNK，这导致 AP-1蛋白c-Fos和JunB诱导减少，这两种蛋白都 是5‘IL-2基因增强子反式激活的关键。北美自由贸易协定， 另一方面，它可以在无能T细胞中被激活。一致 利用这一点，除IL-2(例如，IL-4)之外的淋巴因子可以被诱导 不同程度的CD40L表达，无能T细胞可以 仍然在体外刺激B细胞生长和分化。最后， 对这些克隆的T细胞的研究有助于理解这种调节 死亡抑制蛋白Bcl2和Bclx。最近的工作是 建立了T细胞耐受的体内模型，其特征表明 克隆性无能的诱导。TCR转基因T细胞恢复 在没有佐剂的情况下暴露于可溶性抗原的动物 表现出不能产生IL-2。在实验中 在这一应用中，这些耐受性T细胞将被研究 在体外和体内寻找信号转导缺陷的证据并 评估他们参与抗体和细胞介体的能力 免疫反应。此外，它们的生存特征 耐受性T细胞将被检测，这将与它们的 多种死亡抑制蛋白和效应蛋白的表达。最后，一个 抗原诱导的关节炎模型将测试这种方法的能力 诱导T细胞耐受以预防AN的发展 炎症性疾病。所获得的数据将扩大我们的 对外周自我耐受性调节的理解 在该计划项目下，以及作为基础的 人类问题治疗方法的发展 自身免疫性疾病。

Immune tolerance to peripheral self-antigens in vivo depends on the combined effects of several mechanisms: clonal anergy, deletion, suppression, and clonal ignorance. Each mechanism is antigen- specific; therefore, an understanding of their underlying nature could serve as a foundation for the design of rational strategies for the treatment of autoimmune diseases. Work under this project in the past has focused on the regulation of immune responsiveness by the clonal anergy mechanism using cloned CD4 plus T cells. Our experiments revealed that clonal anergy inhibits T-cell growth not only by blocking secretion of an autocrine growth factor, but also by blocking the up-regulation of lymphokine responsiveness. Clonal anergy was found to be associated with a defect that prevents signals from reaching the MAP kinases ERK and JNK, and that results in reduced induction of the AP-1 proteins c-Fos and JunB, both of which are critical for transactivation at the 5' IL-2 gene enhancer. NAFTp, on the other hand, could be activated in anergic T cells. Consistent with this, lymphokines other than IL-2 (e.g., IL-4) could be induced to various degrees, as could CD40L expression, and anergic T cells could still stimulate B cells to grow and differentiate in vitro. Finally, the study of these cloned T cells led to an understanding of the regulation of the death-repressor proteins Bcl-2 and Bcl-x. More recent work has established an in vivo model of T-cell tolerance with features indicative of the induction of clonal anergy. TCR transgenic T cells recovered from animals exposed to soluble antigen in the absence of adjuvant demonstrate an inability to produce IL-2. In the experiments proposed in this application, these tolerant T cells will be studied both in vitro and in vivo for evidence of signal transduction defects and to assess their capacity to participate in both antibody- and cell-mediate immune responses. Furthermore, the survival characteristics of the tolerant T cells will be examined, and this will be correlated with their expression of various death-repressor and -effector proteins. Finally, an antigen-induced arthritis model will test the capacity of this method of T-cell tolerance induction to prevent the development of an inflammatory disease. The data obtained will expand our understanding of the regulation of peripheral self-tolerance, as pursued under this program project, as well as serve as a basic for the development of therapeutic approaches to the problem of human autoimmune disease.