IL-2 Dependent Processes in Regulatory T cells

 描述（由申请方提供）：CD 4 + Foxp 3+调节性T细胞（T细胞）在免疫耐受中发挥重要作用，可抑制在胸腺发育期间逃避阴性选择的自身反应性T细胞。Foxp 3基因的失活突变是TclO的谱系特异性转录因子，可导致小鼠和人类致命的多器官自身免疫。在患者和动物模型中的研究表明，TGFAP的数量或功能缺陷是许多流行的自身免疫性疾病（如1型糖尿病、系统性红斑狼疮和类风湿性关节炎）的一个促成因素。Treg功能障碍对于移植物抗宿主病（GvHD）背景下耐受性的破坏也是至关重要的，GvHD是造血干细胞移植后供体T细胞针对受体组织的常见且潜在致命的免疫反应。由于Treg缺陷涉及多种自身免疫和同种免疫病症的发病机制，因此能够增强Treg增殖和抑制活性的免疫调节剂已经吸引了相当大的治疗兴趣。细胞因子白细胞介素-2（IL-2）已成为这项研究的最核心的试剂。T细胞的特征是表达高水平的IL-2受体α链（CD 25），使它们能够响应比其他T细胞谱系低得多的IL-2浓度。来自体外研究、动物模型和早期人体试验的大量证据已经确定，以低剂量施用IL-2可以诱导Treg区室的选择性增殖和活化，具有有希望的临床益处。然而，这种疗法的关键参数，如剂量-反应关系，给药方案和治疗持续时间仍未得到解决。 实现这种治疗的全部潜力将需要改进我们对IL-2如何影响成熟THBG生物学的知识。为了直接收集关于这个问题的数据，本研究依赖于CD 25条件性敲除的创新方法，该方法是他莫昔芬诱导的，并且对Foxp 3表达细胞具有特异性。利用这种有效的Treg靶向机制在预定的时间点破坏IL-2受体功能，将有可能获得对组成性IL-2信号对外周成熟Treg的稳态维持、谱系稳定性和活化状态的影响的新见解。我们假设，在废除IL-2 R信号传导后，C57 BL/6小鼠的成熟TCRs将显示通过稳态增殖维持其数量的能力降低，Foxp 3表达的保真度降低，以及分化为高度活化的效应子样细胞表型的能力降低。阐明IL-2在这些过程中的作用，将在不断努力开发IL-2治疗作为一种安全有效的临床免疫抑制策略中有许多应用。

 DESCRIPTION (provided by applicant): CD4+Foxp3+ regulatory T cells (Tregs) play an essential role in immune tolerance, acting to suppress autoreactive T cells that escape negative selection during thymic development. Inactivating mutations in the Foxp3 gene, the lineage-specifying transcription factor for Tregs, cause fatal multi-organ autoimmunity in mice and humans. Research in patients and animal models has implicated numerical or functional deficits in Tregs as a contributing factor in many prevalent autoimmune diseases such as type 1 diabetes, systemic lupus erythematosus, and rheumatoid arthritis. Treg dysfunction is also crucial to the breakdown of tolerance in the setting of graft-versus-host disease (GvHD), a common and potentially fatal immune reaction of donor T cells against recipient tissues following hematopoietic stem cell transplantation. Because Treg defects are involved in the pathogenesis of diverse autoimmune and alloimmune disorders, immunomodulatory agents capable of enhancing Treg proliferation and suppressive activity have attracted considerable therapeutic interest. The cytokine interleukin-2 (IL-2) has emerged as the agent most central to this investigation. Tregs characteristically express high levels of the IL-2 receptor α-chain (CD25), allowing them to respond to much lower concentrations of IL-2 than other T cell lineages. A large body of evidence from in vitro studies, animal models, and early human trials has established that administering IL-2 at low doses can induce selective proliferation and activation of the Treg compartment, with promising clinical benefits. However, critical parameters of this therapy such as dose-response relationship, administration schedule, and treatment duration remain unresolved. Realizing the full potential of this treatment will require improvements in our knowledge of how IL-2 influences the biology of mature Tregs. To gather data on this question directly, this study relies upon the innovative approach of a CD25 conditional knockout that is tamoxifen-inducible and specific for Foxp3- expressing cells. Utilizing this efficient, Treg-targeted mechanism to disrupt IL-2 receptor function at a predetermined point in time, it will be possible to gain novel insights into the impact of constitutive IL-2 signals on the homeostatic maintenance, lineage stability, and activation status of mature Tregs in the periphery. We hypothesize that, following abrogation of IL-2R signaling, the mature Tregs of C57BL/6 mice will show a diminished capacity to sustain their numbers through homeostatic proliferation, reduced fidelity of Foxp3 expression, and a reduced ability to differentiate into highly activated, effector-like cellular phenotypes. Clarifying the role of IL-2in these processes will have numerous applications in the ongoing effort to develop IL-2 therapy as a safe and effective strategy for clinical immunosuppression.