IL-2 Dependent Processes in Regulatory T cells

 描述(申请人提供)：CD4+Foxp3+调节性T细胞(Tregs)在免疫耐受中发挥重要作用，在胸腺发育过程中抑制逃避负选择的自身反应性T细胞。Foxp3基因的失活突变会导致小鼠和人类产生致命的多器官自身免疫。Foxp3基因是Tregs家族特有的转录因子。在患者和动物模型中的研究表明，Tregs的数量或功能缺陷是许多流行的自身免疫性疾病的促成因素，如1型糖尿病、系统性红斑狼疮和类风湿性关节炎。Treg功能障碍也是移植物抗宿主病(GvHD)耐受性崩溃的关键因素，GvHD是造血干细胞移植后供者T细胞对受体组织的一种常见且具有潜在致命性的免疫反应。由于Treg缺陷参与了多种自身免疫性和同种异体免疫性疾病的发病机制，因此能够促进Treg增殖和抑制活性的免疫调节剂已经引起了相当大的治疗兴趣。细胞因子白介素2(IL-2)已经成为这项研究最核心的因素。树突状细胞典型地表达高水平的IL-2受体α链(CD25)，使它们能够对比其他T细胞系低得多的IL-2浓度产生反应。来自体外研究、动物模型和早期人类试验的大量证据表明，低剂量给予IL-2可以诱导Treg区的选择性增殖和激活，具有良好的临床疗效。然而，这种疗法的关键参数，如剂量-反应关系、给药计划和治疗持续时间仍未解决。要实现这种治疗的全部潜力，需要改进我们对IL-2如何影响成熟Treg生物学的知识。为了直接收集关于这个问题的数据，这项研究依赖于CD25条件基因敲除的创新方法，这种方法是他莫昔芬诱导的，并且对Foxp3表达的细胞是特异的。利用这种高效的Treg靶向机制在预定的时间点扰乱IL-2受体的功能，将有可能获得关于结构性IL-2信号对外周成熟Treg的动态平衡维持、谱系稳定性和激活状态的影响的新见解。我们假设，随着IL-2R信号的取消，C57BL/6小鼠的成熟Treg通过稳态增殖维持其数量的能力将减弱，Foxp3表达的保真度降低，分化为高度激活的效应型细胞表型的能力减弱。阐明IL-2在这些过程中的作用将在开发IL-2疗法作为一种安全有效的临床免疫抑制策略的持续努力中有许多应用。

 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.