Memory CD8 T cell localization and protection from influenza

流感感染是一种反复出现的公共卫生负担和我们目前应对季节性流感的策略 接种疫苗提供了次佳的保护。因此，至关重要的是提供对 通用流感疫苗的可能性和大量工作致力于广泛诱导的策略 中和抗体。然而，在没有中和抗体的情况下，IAV特异性的存在 以保守的病毒蛋白为靶点的记忆CD8T细胞，如NP或M2，它们被维持 在系统和肺中都与控制病毒滴度和减少疾病症状有关 人类。小鼠模型表明，正是肺常驻记忆CD8 T细胞(Trm)使快速和 针对IAV感染的强大保护。因此，在肺中建立一个强大的长期TRM种群可能会 成为具有广泛覆盖面的IAV疫苗的重要目标。我们实验室的最新证据表明 与流感感染的反复相遇在肺部产生了深刻的第四(4M)记忆 与原始(1M)记忆Trm相比，提高了肺Trm的耐久性和异型免疫。 我们的长期目标是了解IAV诱导的TRM的生物学以及这些细胞是如何 被操纵以增强免疫力，以帮助开发通用流感疫苗。我们将解决 这一长期目标有以下具体目标： 具体目标1.确定4M与1M IAV特异性肺的耐久性提高的机制 TRM 特定目标2.确定IAV特异性的4M肺Trm是否比1M肺Trm提供更好的每细胞保护 具体目标3.剖析4M与1M IAV特异性CD69 CD103 LN群体的作用

Influenza infection is a recurring public health burden and our current strategies of seasonal influenza vaccination provide suboptimal protection. Thus, it is critical to provide basic, mechanistic insights into the possibility of universal influenza vaccines and much work is devoted to strategies to induce broadly neutralizing antibodies. However, in the absence of neutralizing antibodies, the presence of IAV-specific memory CD8 T cells targeting conserved viral proteins such as NP or M2, which are maintained systemically as well as in the lung correlate with control of viral titers and reduction of disease symptoms in humans. Mouse models suggest it is the lung resident memory CD8 T cells (Trm) that enable swift and robust protection against IAV infection. Thus, establishing a robust long-term Trm population in the lung may be an important goal for an IAV vaccine with broad coverage. Recent evidence from our laboratories shows that repetitive encounter with influenza infection to generate quaternary (4M) memory in the lung profoundly improves the durability of lung Trm and heterosubtypic immunity compared to primary (1M) memory Trm. Our long-term goal is to understand the biology of IAV-induced Trm and how these cells can be manipulated to enhance immunity to aid in development of universal influenza vaccines. We will address this long-term goal with the following specific aims: Specific Aim 1. Determine the mechanisms underlying improved durability of 4M vs 1M IAV-specific lung Trm Specific Aim 2. Determine if IAV-specific 4M lung Trm provide better per cell protection than 1M lung Trm Specific Aim 3. Dissect the role of 4M vs 1M IAV-specific CD69+CD103+ LN populations