IL-2-dependent mechanisms in T1D

描述（由申请人提供）：1型糖尿病（T1 D）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-2 R亚基的多态性是与T1 D相关的重要遗传风险。在NOD小鼠中，Idd 3基因座处的IL-2多态性导致IL-2产生降低，从而导致Tcl 3受损。从概念上讲，这一结果意味着TlD水平上的IL-2 R信号传导缺陷代表了TlD的遗传风险。然而，TlD中改变的IL-2 R信号传导如何促成TlD尚不清楚。用低剂量IL-2治疗小鼠抑制NOD小鼠中的T1 D。这种改善结果的基础除了与增加的TdR产生的明显关联外，还知之甚少。我们最近的工作为低剂量IL-2治疗诱导耐受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。通过开发IL-2 R信号强度不同的小鼠模型，发现Treg发育和稳态需要低IL-2 R信号。因此，低剂量的IL-2对TcB中关键的IL-2依赖性特性产生积极影响。 然而，除了Foxp 3和CD 25的诱导外，关于弱IL-2 R信号转导在TcB中激活的机制知之甚少。为了增加另一层复杂性，我们定义了Tclad中需要更广泛信号传导的其他活动，包括Treg子集的开发。这一提议的一个重要假设是，TcB的关键功能和分子特性将与IL-2 R信号强度相关地不对称地变化。因此，依赖于高IL-2 R信号传导的那些Treg活性最初将受损。这些类型的活动可能影响Treg稳态，但也可能干扰Treg功能，包括它们发展成高度活性的抑制性亚群。慢性低IL-2 R信号传导将损害导致T1 D的其他Treg活性。该提案的主要目标是系统地鉴定作为IL-2 R信号传导受损或IL-2免疫治疗后的结果而在T细胞中变化的IL-2依赖性特性的全范围。这些信息将为更好地了解自身免疫性疾病的潜在IL-2相关风险提供基础，并为成功的基于IL-2的致耐受性治疗提供基础，特别是T1 D。为了检验我们的假设并实现我们的目标，提出了以下目标：1）确定NOD小鼠中受损的IL-2 R信号传导改变Treg和Teff细胞功能的程度，并解释对T1 D的遗传易感性~ 2）确定Treg亚群的发育和稳定性依赖于IL-2 R信号传导的程度以及活化的Teff抑制自身免疫的功能相关性~和3）研究增强的IL-2 R信号传导导致NOD小鼠中T1 D抑制的耐受诱导的基础。 公共卫生相关性：IL-2 R信号传导缺陷与T1 D患者中的TlD相关。低剂量IL-2治疗可提高TcB水平，并促进几种自身反应不受控制的人类疾病的耐受性。从拟议研究中获得的知识可以定义：1）T1 D的潜在IL-2相关风险，2）预测T1 D发作或严重程度的新生物标志物，以及3）预测T1 D成功治疗的机制，包括细胞和分子靶点。由于NOD模型类似于人类T1 D，因此这些信息可能直接转化为T1 D患者。

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.