Lung resident memory CD8+ T cells during viral infections - generation and functionality regulated by localisation and type I IFNs

根据世界卫生组织的数据，每年有300万人死于肺部感染，是死于腹泻病、艾滋病和糖尿病人数总和的两倍多。病毒是许多这些感染的原因，但在发现上呼吸道病毒感染如何传播到肺部并导致肺炎方面的研究投入相对较少。下呼吸道感染最常见的病毒病因是呼吸道合胞病毒（RSV）和甲型流感病毒（IAV），两者都经常引起严重的疾病。尽管在过去60年里做出了巨大的努力，但仍未开发出针对呼吸道合胞病毒的疫苗。目前已有部分有效的IAV疫苗，但每年都需要重新设计，以适应不断进化的IAV新毒株。大多数疫苗都是注射的，并诱导保护性抗体在血液中循环。因此，它们并没有被优化为专门保护肺部或动员肺部驻留的免疫细胞来帮助预防严重疾病。我们对肺驻留免疫细胞如何保护我们免受呼吸道病毒侵害的理解尚不完整，但最近的证据表明，T细胞的一种特殊亚群，即组织驻留记忆T （Trm）细胞，对于快速消除RSV和IAV等病毒至关重要。虽然很可能是这些细胞所处的环境塑造了它们的功能和寿命，但这是如何发生的尚不清楚。我们认为，Trm细胞维持在肺内的特定壁龛中，通过与邻近细胞的相互作用而得到培养。在病毒感染期间，称为I型干扰素（ifn）的必需抗病毒分子大量产生。这些细胞因子可以改变T细胞的行为，但它们在决定Trm细胞功能中的作用尚不清楚。在这个提议中，我们将研究I型ifn如何影响Trm细胞的行为。为了实现这一目标，我们将使用一种新技术来研究培养中的活肺组织切片。这些活切片可以在实验室中用病毒或病毒成分重新刺激，以实现组织驻留细胞及其反应的详细可视化。我们将比较小鼠和人类的切片，研究I型ifn如何影响Trm细胞；他们的生存，功能和定位。因此，这一建议将增加对组织保护性T细胞如何被调节的理解，这将有助于开发利用Trm细胞的潜力来减轻病毒诱导疾病的新疫苗和治疗方法。

According to the World Health Organisation, lung infections kill ~3 million people each year, more than twice the number that die of diarrhoeal diseases, AIDS and diabetes combined. Viruses are responsible for many of these infections, but there is relatively little research investment in discovering how upper respiratory viral infections spread to the lungs and cause pneumonia. The most common viral causes of lower respiratory tract infections are respiratory syncytial virus (RSV) and influenza A virus (IAV), both frequently causing severe disease. Despite a vast effort over six decades, vaccines that elicit protection against RSV are yet to be developed. There are partially effective vaccines against IAV, but they need to be redesigned each year to match the new strains of IAV that constantly evolve. Most vaccines are given as an injection and induce protective antibodies that circulate in the bloodstream. As such, they are not optimised to specifically protect the lung or to mobilise lung-resident immune cells that help protect from severe disease. Our understanding of how lung-resident immune cells defend us against respiratory viruses is incomplete, but recent evidence shows that a special subset of T cells, known as tissue resident memory T (Trm) cells, are critical for rapid elimination of viruses such as RSV and IAV. While it is likely that the environment in which these cells reside shapes their function and life span, it remains unclear how this happens. We believe that Trm cells are maintained in specific niches within the lung where they are nurtured by interactions with neighbouring cells. During viral infection, essential anti-viral molecules called type I interferons (IFNs) are produced in large quantities. These cytokines can alter how T cells behave but their role in determining the function of Trm cells is not known. In this proposal we will study how type I IFNs affect the behaviour of Trm cells. To achieve this, we will use a new technique in which we study live slices of lung tissue in culture. These living slices can be re-stimulated with virus or components of the virus in the lab to enable detailed visualisation of tissue-resident cells and their responses. We will compare slices from mice and humans, investigating how type I IFNs influence Trm cells; their survival, function and localisation. Thus, this proposal will provide increased understanding of how tissue-protective T cells are regulated, which will help the development of new vaccines and treatments that harness the potentials of Trm cells to alleviate viral induced disease.