The impact of aging and thymus regeneration on tissue-resident CD8 T cell responses to viral lung infection and vaccination

摘要 新的冠状病毒，SARS-CoV-2，以及由此产生的冠状病毒传染病2019(新冠肺炎) 在美国造成50多万人死亡。新冠肺炎导致患者死亡率和发病率增加 65岁以上的患者相对较年轻的患者。这与与年龄相关的特征良好的特征一致 对SARS-1、MERS和西尼罗河病毒等病毒感染的反应性降低。同样， 老年人对这些病毒疫苗的反应性下降。因此，加强疫苗接种的途径 老年人的反应能力对于保护最脆弱的人群至关重要。该计划的主要贡献者 随着年龄的增长，免疫功能的丧失是胸腺的萎缩，胸腺是T细胞成熟的主要部位。生产 新的幼稚T细胞的数量取决于胸腺微环境中淋巴系的可获得性。 由于每个T细胞通常具有一种TCR特异性，因此导致的原始T细胞谱系的缩小 胸腺萎缩通过减少幼稚的数量来限制T细胞对新感染的反应的幅度 T细胞能够对特定的抗原产生强烈的反应。一个众所周知的例子是CD8的丧失 小鼠衰老过程中脾和肺中识别免疫优势流感的T细胞。同样，最近 研究表明，幼稚T细胞的丢失会增加老年患者新冠肺炎的严重程度。幼稚T细胞特异性丢失 因为免疫优势表位可能会因老年幼稚T细胞的功能障碍而加剧，这些T细胞确实存在于 年长的动物。例如，功能失调的NP366-374特异的组织驻留记忆T细胞(Trm)反应，这 被认为是由于胸腺萎缩而产生的，最近被证明促进了持久性肺 在感染后60天的病毒性肺炎期间，炎症和加重肺损伤(D.p.I.)在衰老的小鼠身上。 胸腺保留了显著的再生能力，再生增加了流感特异性病毒的数量。 然而，目前尚不清楚胸腺再生是否会影响肺内T细胞的反应。 存活率，或流感或其他病毒病原体的疫苗效力。鉴于最近披露的Trm在年龄中的角色- 相关的病毒性肺炎及其潜在的调节疫苗反应的作用，同样重要的是 了解胸腺再生是否会影响老年肺中的Trm群体。我们将评估这些措施的效果 胸腺再生(由生长激素(GH)注射介导)，这是目前正在进行的 人类临床试验)疫苗介导的对病毒性肺炎和继发性CD8 T细胞反应的保护 使用了特征明确的小鼠适应流感模型。作为第二个模型，我们已经生成了一个实验性的 基于MVA(改良疫苗安卡拉)的疫苗用于在感染小鼠之前进行免疫- 适应的SARS-CoV-2。

Summary The novel coronavirus, SARS-CoV-2, and the resulting Coronavirus Infectious Disease 2019 (COVID-19) has caused more than 500,000 deaths in the US. COVID-19 causes increased mortality and morbidity in patients over 65 years of age relative to younger patients. This is consistent with well-characterized age-associated decreases in responsiveness to viral infections such as SARS-1, MERS, and West Nile Virus. Likewise, responsiveness to vaccines for these viruses decline in the elderly. Therefore, approaches to enhance vaccine responsiveness in the elderly are critical to protect the most vulnerable population. A major contributor to the loss of immunocompetence with age is the atrophy of the thymus, the primary site of T cell maturation. Production of new naïve T cells depends on the availability of lymphopoietic niches within the thymic microenvironment. Since each T cell generally has one TCR specificity, the narrowing of the naïve T cell repertoire that results from thymic atrophy restricts the magnitude of the T cell response to new infections by reducing the number of naïve T cells capable of mounting a robust response against a given antigen. A well-known example is the loss of CD8 T cells recognizing an immunodominant influenza in the spleen and lungs during aging in mice. Likewise, recent work suggests loss of naïve T cells increases COVID-19 severity in elderly patients. Loss of naïve T cells specific for immunodominant epitopes may be exacerbated by dysfunction of the aged naïve T cells that do persist in older animals. For example, dysfunctional NP366-374-specific tissue-resident memory T cell (Trm) responses, which were suggested to arise as a result of thymus atrophy, were recently shown to promote persistent lung inflammation and exacerbate lung damage during viral pneumonia at 60 days post infection (d.p.i.) in aged mice. The thymus retains a remarkable capacity to regenerate, and regeneration increases the number of flu-specific T cells in aged spleen, however, it is not known whether thymic regeneration affects T cell responses in the lung, survival, or vaccine efficacy for flu, or other viral pathogens. Given the recently revealed role for Trm in age- associated viral pneumonia, and their potential role mediating vaccine responses, it is also important to understand whether thymic regeneration impacts the Trm population in aged lungs. We will evaluate the effect of thymus regeneration (mediated by Growth Hormone (GH) administration, an approach currently used in ongoing human clinical trials) on vaccine-mediated protection from viral pneumonia and secondary CD8 T cell responses using the well-characterized mouse-adapted flu model. As a second model, we have generated an experimental vaccine based on MVA (Modified Vaccinia Ankara) to be used for immunization ahead of infection with mouse- adapted SARS-CoV-2.