IL-2-dependent mechanisms in T1D

描述(申请人提供)：1型糖尿病(T1D)是一种由自身反应性T细胞介导的自身免疫性疾病。这种复杂的疾病取决于遗传风险因素和环境触发因素。IL-2或IL-2R亚基基因多态性是与T1D相关的重要遗传风险。在NOD小鼠中，Idd3基因上IL-2基因的多态导致IL-2产量降低，导致Treg受损。从概念上讲，这一结果意味着Tregs水平的IL-2R信号缺陷代表着T1D的遗传风险。然而，Tregs中IL-2R信号的改变对T1D的影响还知之甚少。小剂量IL-2治疗可抑制NOD小鼠的T1D。这一改善结果的基础除了与Tregs产量增加明显相关外，人们还知之甚少。我们最近的工作为小剂量IL-2治疗诱导耐受的成功提供了初步的机制洞察，并为拟议的研究提供了一些理论基础。通过建立IL-2R信号强度不同的小鼠模型，Treg的发育和动态平衡被发现需要低IL-2R信号。因此，低剂量的IL-2对Treg的关键的IL-2依赖特性有积极的影响。然而，除了诱导Foxp3和CD25外，弱IL-2R信号在Tregs中的激活机制知之甚少。为了增加另一层复杂性，我们在Treg中定义了其他需要更广泛的信令的活动，包括Treg子集的开发。这一建议的一个重要假设是，Tregs的关键功能和分子特性将随着IL-2R信号强度的不同而不同。因此，依赖于高IL-2R信号的Treg活性最初将受到损害。这些类型的活动可能会影响Treg的动态平衡，但也可能干扰Treg的功能，包括它们发展成一个高度活跃的抑制亚群。慢性低IL-2R信号将损害导致T1D的其他Treg活动。这项建议的主要目标是系统地确定由于IL-2R信号受损或IL-2免疫治疗后在Treg中发生变化的各种IL-2依赖特性。这些信息将为更好地了解自身免疫性疾病潜在的IL-2相关风险提供基础，并为成功的基于IL-2的耐受治疗，特别是T1D提供基础。为了验证我们的假设并实现我们的目标，我们提出了以下目标：1)确定NOD小鼠IL-2R信号受损改变Treg和TJeff细胞功能的程度，并解释T1D~2的遗传易感性；2)确定Treg亚群的发育和稳定性在多大程度上依赖于IL-2R信号以及激活的Treg抑制自身免疫的功能相关性；3)研究IL-2R信号增强导致NOD小鼠对T1D抑制耐受诱导的基础。

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) is an autoimmune disease mediated by self-reactive T cells. This complex disorder depends on genetic risk factors and environmental triggers. Polymorphisms in IL-2 or IL-2R subunits are important genetic risks that are associated with T1D. In NOD mice, polymorphisms in IL-2 at the Idd3 locus results in lower IL-2 production leading to impaired Tregs. Conceptually, this result implies that defective IL-2R signaling at the level of Tregs represents a genetic risk in T1D. Nevertheless, how altered IL-2R signaling in Tregs contribute to T1D is poorly understood. Treatment of mice with low dose IL-2 suppresses T1D in NOD mice. The basis for this improved outcome is poorly understood other than an obvious association with increased production of Tregs. Our recent work offers an initial mechanistic insight for the success of low dose IL-2 therapy for tolerance induction and provides some of the rationale for the proposed studies. By developing mouse models that vary in IL-2R signaling strength, Treg development and homeostasis were found to require low IL-2R signaling. Thus, critical IL-2-dependent properties in Tregs are positively affected by low dose IL-2. However, other than induction of Foxp3 and CD25, little is known concerning the mechanisms activated in Tregs by weak IL-2R signaling. To add another layer of complexity, we have defined other activities in Tregs that require more extensive signaling, including the development of Treg subsets. An important hypothesis for this proposal is that key functional and molecular properties of Tregs will vary asymmetrically in relationship to IL-2R signaling intensity. Accordingly, those Treg activities dependent on high IL-2R signaling will initially be impaired. These types of activities might affect Treg homeostasis but also likely interfere with Treg function, including their development into a highly active suppressive subset. Chronic low IL-2R signaling will then impair other Treg activities that lead to T1D. Major objectives of this proposal are to systemically identify the full range of IL-2-dependent properties that vary in Tregs as a consequence of impaired IL-2R signaling or after IL-2 immunotherapy. Such information will provide a foundation to better understand the underlying IL-2- related risk for autoimmune disease and the basis for successful IL-2-based tolerogenic therapy in general and for T1D in particular. To test our hypotheses and achieve our objectives, the following aims are proposed: 1) To determine the extent that impaired IL-2R signaling in NOD mice alters the function of Treg and Teff cells and accounts for the genetic susceptibility to T1D~ 2) to establish the extent the development and stability of Treg subsets depend on IL-2R signaling and the functional relevance of activated Tregs to suppress autoimmunity~ and 3) to investigate the basis by which enhanced IL-2R signaling leads to tolerance induction for suppression of T1D in NOD mice.