Homeostasis and function of regulatory T cells in aging

描述（由申请人提供）：免疫功能下降在老年人中得到了很好的描述，并显著增加了感染的风险和严重程度，降低了对疫苗接种的反应，以及对癌症的控制较差。几种病原体的感染，无论是病毒性（如疱疹病毒）、细菌性（如分枝杆菌）还是寄生性（如利什曼原虫），都会在宿主的一生中持续存在。这种持续性感染的重新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CD4+ T细胞的一个特殊亚群，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负向调节免疫反应，但目前尚不清楚它们的积累是否会对老年人的免疫功能产生负向影响。我们在老年人和利什曼原虫感染小鼠模型中的初步数据表明，Treg积极抑制效应T细胞的功能。我们的初步数据还表明，Treg消耗增加了体外衰老的人类巨细胞病毒（CMV）特异性T细胞反应。此外，在小鼠CMV （MCMV）感染的幼鼠中，Treg缺失显著增加了MCMV特异性T细胞的体内反应。尽管Treg可能随着年龄的增长而导致免疫抑制，但Treg在老年人中积累的机制尚不清楚。我们的初步数据表明，Treg在小鼠体内的积累是进行性的，是由小鼠对细胞凋亡的抵抗力增强引起的。更具体地说，我们发现(i) Treg中促凋亡分子Bim的水平正常且随着年龄的增长而逐渐下降；（ii）在没有Bim的情况下，Treg积累得更快；（iii） IL-2和IL-15起部分冗余作用

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.