The impact of senescence on immune memory

项目摘要 众所周知，免疫系统中与年龄相关的变化有助于降低免疫系统的免疫能力。 在感染或接种疫苗后产生高度保护性反应。虽然接种疫苗确实可以改善结果， 在老年人中，流感仍然是所有导致死亡的传染病中最重要的， 这一人群的残疾。重要的是，衰老影响了适应性免疫反应的几乎每个方面， 包括产生病毒特异性CD 4和CD 8 T细胞效应子，产生高亲和力抗体 和保护性免疫记忆的产生。老龄化最突出的一个特点就是积累 衰老细胞（SC）在各种组织中的作用，在这个项目中，我们将探讨SC在塑造衰老细胞中的作用。 流感病毒感染后保护性免疫记忆的产生。 细胞衰老的特征在于当细胞经历应激时发生的不可逆的生长停滞。 衰老在成年人中有两个主要作用：一个是抑制已经引起DNA或其他损伤的细胞， 防止它们转化为癌症，另一个是帮助伤口愈合。虽然SC被有效清除， 年轻人的免疫系统，随着年龄的增长，情况就不是这样了。随着年龄的增长， 衰老细胞的数量增加，导致许多与年龄相关的病理和疾病。此外，因素 衰老相关分泌表型（Senescence Associated Secretory Phenotype，SASP）也可以与衰老细胞的分泌有关。 对周围细胞的影响导致功能障碍和错误的分化。 在这个项目中，我们将使用两个实验模型来研究SC对免疫应答的影响 流感病毒感染后产生的免疫记忆，重点是保护性免疫记忆的产生。一是 在Campisi实验室开发的p16-Tripommodality Reporter（p16- 3 MR）转基因小鼠模型和第二个 是用senolytics治疗老年C57 BL/6小鼠。重要的是，我们的初步研究表明， 在流感感染前消除老年小鼠中的SC对保护性免疫的产生有负面影响， 记忆该提案的目标是进一步探索老年小鼠中SC的缺失如何影响免疫力， 从效应阶段过渡到持久保护性记忆的产生。该提案具有高度 翻译的意义，因为临床试验的senolytics对传染病，如COVID-19， 已经在进行中，重要的是要确定这种治疗是否会损害保护性记忆的形成， 使处于危险中的老年人面临严重再感染的风险。

PROJECT SUMMARY It is well known that age-related changes in the immune system contribute to declines in the ability to mount a highly protective response following either infection or vaccination. While vaccination does improve the outcome of influenza (flu) infection in older adults, it is still foremost among all infectious diseases causing death and disability in this population. Importantly, aging impacts almost every aspect of the adaptive immune response to influenza including generation of virus-specific CD4 and CD8 T cell effectors, high affinity antibody production and generation of protective immune memory. One of the most prominent features of aging is the accumulation of senescent cells (SC) in various tissues and in this project, we will explore the role of SC in shaping the generation of protective immune memory following influenza infection. Cellular senescence is characterized by irreversible growth arrest that occurs when cells experience a stressor. Senescence has two main roles in an adult: one is to suppress cells that have incurred DNA or other damage to prevent them from transitioning into cancer, the other is to aid in wound healing. While SC are efficiently cleared by the immune system in young individuals, this is not the case as we get older. With chronological aging, the number of senescent cells increases, resulting in many age-related pathologies and diseases. In addition, factors secreted by senescent cells (the Senescence Associated Secretory Phenotype, SASP) can also have a direct impact on surrounding cells driving dysfunction and misdirected differentiation. In this project, we will use two experimental models to examine the impact of SC on the immune responses generated following an influenza infection, with a focus on generation of protective immune memory. The first is the p16-Trimodality Reporter (p16-3MR) transgenic mouse model developed in the Campisi lab and the second is the treatment of aged C57BL/6 mice with senolytics. Importantly, our preliminary studies have shown that eliminating SC in aged mice prior to flu infection has a negative impact on the generation of protective immune memory. The goal of this proposal is to further explore how deleting SC in aged mice impacts immunity and the transition from the effector phase to the generation of durable protective memory. This proposal has high translational significance as clinical trials for the senolytics for infectious diseases, such as COVID-19, are already underway and it is important to determine if this treatment could impair protective memory formation and leave at-risk older adults at risk for severe reinfection.