The impact of senescence on immune memory

项目总结 众所周知，免疫系统中与年龄有关的变化会导致免疫功能下降。 感染或接种疫苗后的高度保护性反应。虽然接种疫苗确实可以改善结果 在老年人感染流感的情况下，它仍然是所有导致死亡和 这一人群中的残疾。重要的是，衰老几乎影响适应性免疫反应的方方面面 流感包括产生病毒特异性的CD4和CD8T细胞效应器，产生高亲和力抗体 以及保护性免疫记忆的产生。衰老的一个最突出的特征就是积累 衰老细胞(SC)在不同组织中的变化，在这个项目中，我们将探索SC在塑造 流感感染后保护性免疫记忆的产生。 细胞衰老的特征是当细胞经历应激源时发生不可逆转的生长停滞。 衰老在成年人中有两个主要作用：一个是抑制引起DNA或其他损伤的细胞 防止他们转化为癌症，另一个是帮助伤口愈合。当SC被有效地清除时 在年轻人的免疫系统中，随着我们年龄的增长，情况并非如此。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 由衰老细胞(衰老相关分泌表型，SASP)分泌的也可以直接 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检查SC对免疫反应的影响 在流感感染后产生，重点是产生保护性免疫记忆。第一个是 Campisi实验室开发的p16-Trimodality Reporter(p16-3MR)转基因小鼠模型和第二个 是用感觉剂治疗衰老的C57BL/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龄小鼠的SC对保护性免疫的产生有负面影响 记忆。这项建议的目的是进一步探讨删除衰老小鼠的SC对免疫力的影响，以及 从效应器阶段过渡到产生持久的保护性记忆。这项建议有很高的 翻译意义作为传染病的感觉剂的临床试验，如新冠肺炎，是 已经在进行中，确定这种治疗是否会损害保护性记忆的形成和 使高危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.