Understand the molecular mechanism of age-associated decline in antiviral CD8 T cell immunity

摘要 免疫衰老会增加感染后的发病率和死亡率，并降低疫苗效力。死亡人数最多 与感染流感病毒、SARS-CoV或SARS-CoV-2有关的病例发生在65岁以上的人群中。因此， 了解与年龄相关的抗病毒免疫下降的机制对发展抗病毒免疫至关重要 保护老年人免受病毒病原体侵袭的策略。尽管它在预防感染方面发挥了关键作用，但T- 细胞免疫力随着年龄的增长而下降。在衰老过程中，幼稚T细胞的患病率下降，而 终末分化的CD8T细胞比例增加。此外，衰老会降低幼稚T细胞的反应性 与抗原有关。然而，与年龄相关的抗病毒T细胞免疫下降的分子机制 仍然没有明确的定义。使用小鼠肝炎病毒(MHV)感染的小鼠模型，我们发现衰老 死亡率增加，抗病毒CD4和CD8T细胞应答降低。令人惊讶的是，尽管年龄越来越大 在基线水平，终末分化的CD8 T细胞增加，终末分化的CD8 T细胞显著减少 分化效应CD8 T细胞与MHV后老年小鼠T细胞耗竭的基因标志 感染。此外，我们还表明，与年龄相关的T细胞扩张性下降主要是由TCR- 触发了细胞凋亡和坏死性下垂通路，并通过重新平衡TCR和IL2信号被拯救。我们也 研究发现，衰老降低了T细胞的代谢率，损害了T细胞的代谢适应 在激活之后。在这里，我们假设与年龄相关的疲惫倾向表观遗传状态和缺陷 病毒感染时代谢适应损害效应分子CD8 T细胞反应。在这项研究中，我们将定义 抗病毒CD8T细胞的表观遗传和代谢途径在感染前后随着年龄的变化而改变，而 说明了与年龄相关的分化变化。我们还将评估利用IL2和 TCR途径修复抗病毒CD8 T细胞的年龄相关缺陷。

Summary Immunosenescence increases morbidity and mortality after infection and reduces vaccine efficacy. Most deaths associated with infections by influenza virus, SARS-CoV, or SARS-CoV-2 occurred in people older than 65. Thus, understanding the mechanism of age-associated decline in antiviral immunity is critical to the development of strategies to protect the elderly from viral pathogens. Despite its critical role in protection against infections, T- cell immunity declines with age. During aging, the prevalence of naïve T cells decreases, whereas the frequency of terminally differentiated CD8 T cells increases. In addition, aging reduces the responsiveness of naïve T cells to antigen. However, the molecular mechanism underlying age-associated decline in antiviral T cell immunity remains poorly defined. Using a mouse model of murine hepatitis virus (MHV) infection, we found that aging increased mortality and decreased antiviral CD4 and CD8 T cell responses. Surprisingly, although aging increased terminally differentiated CD8 T cells at baseline, there was a profound reduction in terminally differentiated effector CD8 T cells and an elevated gene-signature of T-cell exhaustion in aged mice after MHV infection. In addition, we showed that age-associated decline in T-cell expansion was primarily caused by TCR- triggered apoptosis and necroptosis pathways and was rescued by rebalancing TCR and IL2 signaling. We also found that aging reduced the metabolic rate of T cells at baseline and impaired metabolic adaptation of T cells after activation. Here, we hypothesize that age-associated exhaustion-prone epigenetic state and defective metabolic adaptation impair effector CD8 T cell response in viral infection. In this study, we will define the epigenetic and metabolic pathways in antiviral CD8 T cells altered by aging before and after infection, while accounting for age-associated changes in differentiation. We will also evaluate strategies that harness IL2 and TCR pathways to rescue age-related defects in antiviral CD8 T cells.