Homeostasis and function of regulatory T cells in aging

描述（由申请方提供）：免疫功能下降在老年人中有很好的描述，并显著增加感染的风险和严重程度，对疫苗接种的反应受损，以及癌症控制较差。感染多种病原体，无论是病毒性的（例如，疱疹病毒），细菌（例如，分枝杆菌）或寄生菌（例如，利什曼原虫，坚持一辈子的宿主。这种持续性感染的再激活是老年人免疫功能减弱的常见后果。 调节性T细胞（Treg）是CD 4 + T细胞的一个特化亚群，已被证明可以控制免疫反应的强度，随着年龄的增长而急剧积累。虽然Treg负调节免疫反应，但目前尚不清楚它们的积累是否对老年人的免疫功能有负面影响。我们在老年人和大型利什曼原虫感染小鼠模型中的初步数据显示，Treg积极抑制效应T细胞的功能。我们的初步数据还表明，Treg耗竭增加体外老年人巨细胞病毒（CMV）特异性T细胞应答。此外，在鼠CMV（MCMV）感染的年轻小鼠中，Treg耗竭显著增加体内MCMV特异性T细胞应答。虽然Treg可能有助于随着年龄的增长而产生免疫抑制，但老年人中Treg积累的潜在机制仍不清楚。我们的初步数据表明，Treg在小鼠中的积累是进行性的，是由它们对凋亡的抵抗力增加引起的。更具体地说，我们发现（i）Treg中促凋亡分子Bim的水平随着年龄的增长而正常地和进行性地降低;（ii）在Bim不存在的情况下，Treg积累更快;（iii）IL-2和IL-15在Treg中起部分冗余的作用。 （iv）Bim的额外损失恢复了老年IL-15缺陷小鼠中Treg的损失;（v）叉头盒转录因子亚类0（FOXO）成员1、3a和4的急性体内损失导致Treg中Bim表达降低。总之，我们的数据表明，慢性细胞因子信号通过增强FOXO 3a依赖性抑制Bim表达来增加Treg的体内存活的模型。 我们的总体假设是，Treg在老年小鼠和人类中的累积是由于烟碱驱动的Bim表达抑制，并有助于免疫抑制和病原体持续存在。该假设将在三个特定目的中进行测试：（1）：定义老年宿主中Treg积累增加的机制;（2）定义两种持续感染模型（大型利什曼原虫和MCMV）中Treg的稳态和功能;（3）确定Bim/FOXO轴是否控制人类中Treg的存活以及Treg在抑制老年人中CMV特异性T细胞应答中的作用。这项研究的长期目标是确定Treg在衰老免疫抑制中的作用，并设计新的治疗方法来增强老年人的感染控制和疫苗效力。

DESCRIPTION (provided by applicant): Declining immune function is well described in the elderly, and contributes significantly to increased risk and severity of infection, impaired responses to vaccination, and poorer control of cancer. Infections with several pathogens, whether viral (e.g., herpes viruses), bacterial (e.g., Mycobacteria) or parasitic (e.g., Leishmania, persist for the lifetime of the host. Reactivation of such persistent infections is a common consequence of waning immune function in the elderly. Regulatory T cells (Treg), a specialized subset of CD4+ T cells that have been shown to control the intensity of immune responses accumulate dramatically with age. While Treg negatively regulate immune responses, it is currently unclear whether their accumulation contributes negatively to immune function in the elderly. Our preliminary data in elderly humans and in a mouse model of Leishmania major infection show that Treg actively suppress the functionality of effector T cells. Our preliminary data also show that Treg depletion increases aged human cytomegalovirus (CMV)-specific T cell responses in vitro. In addition, in murine CMV (MCMV)- infected young mice, Treg depletion significantly increased MCMV-specific T cell responses in vivo. Although Treg likely contribute to immunosuppression with age, the mechanisms underlying Treg accumulation in the elderly remain unclear. Our preliminary data suggest that Treg accumulation in mice is progressive and is caused by their increased resistance to apoptosis. More specifically, we found that (i) levels o the pro-apoptotic molecule Bim in Treg are normally and progressively decreased with age; (ii) in the absence of Bim, Treg accumulate faster; (iii) IL-2 and IL-15 play a partially redundant role in driving Treg accrual in aged mice; (iv) the additional loss of Bim restores the loss of Treg in aged IL-15-deficient mice; (v) acute, in vivo loss of forkhead box transcription factor subclass O (FOXO) members 1, 3a, and 4 lead to decreased expression of Bim in Treg . Together, our data suggest a model in which chronic cytokine signaling increases in vivo survival of Treg by enhancing FOXO3a-dependent suppression of Bim-expression. Our overarching hypothesis is that accrual of Treg in aged mice and humans are due to cytokine-driven repression of Bim expression and contributes to immunosuppression and pathogen persistence. This hypothesis will be tested in three Specific Aims: (1): Define the mechanisms of increased accumulation of Treg in aged hosts; (2) Define the homeostasis and functionality of Treg in two models of persistent infection, Leishmania major and MCMV; (3) Determine if a Bim/FOXO axis controls Treg survival in humans and the role of Treg in dampening CMV-specific T cell responses in elderly humans. The long-term aim of this research is to determine the role of Treg in the immune suppression of aging, and to devise novel therapeutic approaches to enhance infection control as well as vaccine efficacy in the elderly.