Cutaneous pathogen-specific tissue resident memory T cells in human aging

项目摘要： 免疫力下降对老年人的发病率和死亡率有重大影响。 抗原特异性的、获得性的，特别是T细胞的在宿主防御中是重要的， 慢性细胞内病原体和癌症。感染这些微生物和皮肤 具有高突变负荷和新表位负荷的癌症， 在老年人中。在这个应用程序中，调查小组使用一个既定的四聚体 和TCR工具包，用于研究水痘带状疱疹病毒感染的T细胞应答 (VZV)以确定与年龄相关的带状疱疹易感性的机制， 以及一种独特的成功疫苗的作用机制， 老人 最近，人们已经认识到，宿主对许多局部感染的防御 是由特殊群体的组织驻留记忆细胞（简称TRM）介导的。作为 小鼠和人类的研究已经取得进展，TRM的谱系，TRM亚群，以及TRM的基因表达。 TRM在各种组织中的转录和代谢特征已经开始出现 成为焦点。TRM是局部移动的，巡逻组织以寻找抗原，并且可以在 抗原重新暴露，但不会重新进入血液，并且是血液接触不到的。 问题研究值得注意的是，人抗原特异性TRM的研究是罕见的，使得检测TRM的测定是不可能的。 总的TRM人群可能忽略了TRM的复杂性。 在这里，我们使用VZV感染和疫苗接种作为TRM T细胞的相关探针， 年龄谱。目的1关注VZV的内源性再激活，并使用活检 愈合的带状疱疹和控制皮肤，第一次，完全描述了有益的人类 病毒特异性TRM在单细胞水平。Aim 2使用新的RZV疫苗治疗带状疱疹 预防，即使在老年人中也保持有效性，以确定疫苗是否会导致 TRM接种在皮肤中，改善归巢定向细胞库， 血，或者两者。总之，这些研究将增加我们对年龄的理解- 重要效应T细胞的相关变化和可能有助于克服的策略 免疫衰老

Project Summary: The waning of immunity has a major impact on morbidity and mortality in the aged. Antigen-specific, acquired, and especially T-cellular is important in host defense against chronic intracellular pathogens and cancer. Infections with these microbes and skin cancers with high mutational burdens and neoepitope loads, are disproportionally high in the elderly. In this application, the investigative team uses an established tetramer and TCR toolkit for the study of T-cell responses to varicella zoster virus infections (VZV) in humans to determine the mechanisms of age-related susceptibility to shingles, and the mechanisms of action of a uniquely successful vaccine that retains efficacy in the elderly. Recently, it has been appreciated that host defense against many localized infections is mediated by special populations of tissue resident memory cells, abbreviated TRM. As murine and human studies have advanced, the lineage of TRM, TRM subsets, and the transcriptional and metabolic signature of TRM in various tissues have begun to come into focus. TRM are locally mobile, patrol tissue for antigen, and can proliferate upon antigen re-exposure, yet do not re-enter the blood and are out of reach of blood-based studies. Notably, studies of human antigen-specific TRM are rare, such that assays of overall TRM populations may overlook the complexity of TRM. Here, we use VZV infection and vaccination as related probes of TRM T-cells across the age spectrum. Aim 1 focuses on endogenous reactivation of VZV and uses biopsies of healed shingles and control skin to, for the first time, fully characterize helpful human virus-specific TRM at the single cell level. Aim 2 uses the new RZV vaccine for shingles prevention, which retains efficacy even in aged adults, to determine if the vaccine leads to TRM seeding in the skin, improvement in the pool of homing-committed cells in the blood, or both. Taken together, these studies will increase our understanding of age- related changes in vital effector T-cells and strategies that may be useful to overcome immune senescence.