IL-2-dependent mechanisms in T1D

描述（由申请人提供）：1型糖尿病（T1D）是由自身反应性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亚基多态性是与T1D相关的重要遗传风险。在NOD小鼠中，Idd3位点的IL-2多态性导致IL-2产生降低，从而导致Tregs受损。从概念上讲，这一结果表明Tregs水平上的IL-2R信号缺陷代表了T1D的遗传风险。然而，Tregs中IL-2R信号的改变如何导致T1D尚不清楚。低剂量IL-2可抑制NOD小鼠的T1D。这一改善结果的基础除了与treg产量增加明显相关外，人们对其了解甚少。我们最近的工作为低剂量IL-2诱导耐受治疗的成功提供了初步的机制见解，并为拟议的研究提供了一些基本原理。通过建立IL-2R信号强度变化的小鼠模型，发现Treg的发育和稳态需要低IL-2R信号。因此，低剂量IL-2会积极影响Tregs中关键的IL-2依赖性特性。然而，除了诱导Foxp3和CD25外，关于弱IL-2R信号在Tregs中激活的机制知之甚少。为了增加另一层复杂性，我们在Treg中定义了需要更广泛的信令的其他活动，包括Treg子集的开发。该提议的一个重要假设是Tregs的关键功能和分子特性将与IL-2R信号强度不对称地变化。因此，那些依赖于高IL-2R信号的Treg活性最初会受到损害。这些类型的活动可能会影响Treg稳态，但也可能干扰Treg功能，包括它们发展成一个高度活跃的抑制性亚群。慢性低IL-2R信号会损害导致T1D的其他Treg活性。本提案的主要目标是系统地识别由于IL-2R信号受损或IL-2免疫治疗后Tregs中IL-2依赖性特性的变化。这些信息将为更好地了解自身免疫性疾病中与IL-2相关的潜在风险提供基础，并为基于IL-2的耐受原性治疗（特别是T1D）的成功奠定基础。为了检验我们的假设和实现我们的目标，我们提出了以下目标：1)确定NOD小鼠IL-2R信号通路受损对Treg和Teff细胞功能的改变程度，并解释T1D的遗传易感性~ 2)确定Treg亚群的发育和稳定依赖IL-2R信号通路的程度以及活化Treg抑制自身免疫的功能相关性~ 3)研究IL-2R信号通路增强诱导NOD小鼠耐受抑制T1D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. PUBLIC HEALTH RELEVANCE: Defective IL-2R signaling is associated with Tregs in T1D patients. Low dose IL-2 therapy boosts Tregs and promotes tolerance in several human disorders with uncontrolled self- reactivity. The knowledge gain from the proposed studies may define: 1) an underlying IL-2- related risk for T1D, 2) new biomarkers predictive of the onset or severity of T1D, and 3) the mechanism, including cellular and molecular targets, predictive of successful therapy of T1D. As the NOD model resembles human T1D, there is the potential that such information may be directly translated to individuals with T1D.