Role of NFAT in the Treg-mediated suppression of T helper cell activation

描述(由申请者提供)：区分自我和非自我的能力对于维持适当的免疫平衡是必不可少的。大多数自身反应性T细胞在胸腺中通过负选择被消除；然而，一些携带识别自身蛋白质的T细胞受体的细胞仍然可能逃脱胸腺选择，作为成熟的T细胞进入外周系统。为了避免自身免疫，这些细胞必须被灭活。维持外周耐受的最重要机制之一是调节性T细胞(Treg)的抑制。天然Tregs是在胸腺中产生的，占CD4+T细胞总数的5%-10%。Tregs通过抑制辅助性T细胞和细胞毒性T细胞的细胞因子表达和效应功能来控制自身反应性T细胞。尽管Tregs的功能在过去几年中一直是密集研究的对象，但Tregs灭活T细胞的机制仍未得到充分研究。这项建议的总体目标是阐明Treg介导的效应器T细胞功能失活的分子机制。最近的报道表明，活化T细胞核因子(NFAT)的成员可能通过调节无能的诱导和Tregs的产生而在控制自身反应性T细胞中发挥作用。在这项建议中，我们将确定Tregs与T辅助细胞的相互作用是否也可能导致钙/NFAT依赖的程序的诱导，从而导致T细胞激活的抑制。NFAT蛋白的激活在Treg功能中的作用将在体外和体内进行研究，并分析特定基因表达上调的后果。对Treg介导的抑制效应器T细胞功能的机制的详细了解将为开发新的治疗方法提供有价值的信息，这些新疗法旨在诱导自身免疫性疾病的耐受，防止移植物排斥反应，或在癌症或慢性感染的治疗过程中阻断Treg功能。 与公共健康相关的调节性T细胞已被确定为控制针对我们自身组织的免疫反应的关键调节器。它们的功能对于了解慢性感染和癌细胞如何逃避有效的免疫反应也是至关重要的。这些细胞的功能背后的机制还知之甚少。这个项目的目的是描述调节性T细胞如何调节对其他活性T细胞群的抑制。从该项目中获得的信息将对设计新的治疗方法非常有价值，以控制调节性T细胞在自身免疫、移植排斥和癌症等疾病的治疗中的功能。

DESCRIPTION (provided by applicant): The ability to distinguish self from non-self is essential in maintaining proper immune homeostasis. Most self-reactive T cells are eliminated in the thymus through negative selection; however some cells bearing T cell receptors that recognize self proteins may still escape thymic selection and enter the peripheral system as mature T cells. To avoid autoimmunity, those cells must be inactivated. One of the most important mechanisms involved in the maintenance of peripheral tolerance is suppression by regulatory T cells (Tregs). Natural Tregs are generated in the thymus and constitute 5-10% of the total CD4+ T cell population. Tregs control autoreactive T cells by suppressing cytokine expression and effector functions of T helper and cytotoxic T cells. Although the function of Tregs has been the object of intense research during the last years, the mechanisms responsible for the inactivation of T cells by Tregs remain yet poorly characterized. The overall goal of this proposal is to elucidate the molecular mechanisms underlying Treg mediated inactivation of effector T cell functions. Recent reports have indicated that members of the Nuclear Factor of Activated T cells (NFAT) may play a role in controlling self-reactive T cells by regulating the induction of anergy and the generation of Tregs. In this proposal we will determine if the interaction of Tregs with T helper cells may also result in the induction of a calcium/NFAT-dependent program that leads to the suppression of T cell activation. The role of the activation of NFAT proteins in Treg function will be studied in vitro and in vivo and the consequences of the upregulation of the expression of specific genes analyzed. A detailed understanding of the mechanisms that underlie Treg-mediated suppression of effector T cell function should provide valuable information to develop new therapies designed to induce tolerance in autoimmune disease and to prevent graft rejection, or to block Treg function during the treatment of cancer or chronic infections. PUBLIC HEALTH RELEVANCE Regulatory T cells have been identified as key regulators in the control of immune reactions against our own tissues. Their function is also crucial to understand how chronic infections and cancer cells can evade effective immune responses. The mechanisms that underlie the function of these cells are yet poorly understood. The aim of this project is to characterize how regulatory T cells mediate inhibition of other active T cell populations. The information obtained from this project will be very valuable for the design of new therapeutic approaches to control regulatory T cell function in the treatment of diseases such as autoimmunity, graft rejection and cancer.