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

人类衰老过程中皮肤病原体特异性组织常驻记忆 T 细胞

• 批准号: 10228544
• 负责人: David M Koelle
• 金额: $ 56.18万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228544
• 关键词: Adult; Age; Aging; Animals; Antigens; Biological; Biological Assay; Biopsy; Blood; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Mobility; Cells; Chronic; Clinical; Contralateral; Cranial Nerves; Cutaneous; Data; Deposition; Elderly; Exanthema; Focal Infection; Ganglia; Gene Expression Profile; Genetic Transcription; Herpes zoster disease; Herpesvirus Type 3; Home; Homing; Host Defense; Human; Immune; Immunity; Immunology; Infection; Intramuscular; Intramuscular Injections; Life; Malignant Neoplasms; Measurement; Measures; Mediating; Memory; Metabolic; Methods; Microbe; Molecular Profiling; Morbidity - disease rate; Mus; Mutation; National Institute of Allergy and Infectious Disease; National Institute of Dental and Craniofacial Research; Natural Immunity; Neurons; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Physiological; Population; Positioning Attribute; Predisposition; Prevention; Primary Infection; Proliferating; Proteins; RNA; Recovery; Rejuvenation; Research; Risk; Risk Factors; Route; Simplexvirus; Site; Skin; Skin Cancer; Special Population; Specificity; Subgroup; T cell response; T memory cell; T-Lymphocyte; Time; Tissues; Twin Multiple Birth; VZV vaccine; Vaccination; Vaccines; Viral; Virus; Virus Diseases; acquired immunity; age effect; age related; aged; base; circulating biomarkers; craniofacial; effector T cell; healing; interest; mRNA Expression; mortality; neoantigens; pathogen; prevent; recurrent infection; senescence; tool; vaccine delivery; vaccine development; vaccine discovery; vaccinology

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.

项目总结： 免疫功能的减弱对老年人的发病率和死亡率有重要影响。 抗原特异性，获得性，特别是T细胞在宿主防御中很重要。 慢性细胞内病原体和癌症。感染这些微生物和皮肤 具有高突变负担和新表位负载的癌症高得不成比例 在老年人身上。在此应用程序中，调查团队使用已建立的四聚体 和TCR工具包用于研究T细胞对水痘带状疱疹病毒感染的反应 (VZV)以确定与年龄相关的带状疱疹易感性的机制， 以及一种独一无二的成功疫苗的作用机制 老年人。 最近，人们意识到宿主对许多局部感染的防御 是由特殊的组织驻留记忆细胞群(简称TRM)介导的。AS 小鼠和人类的研究已经取得了进展，TRM、TRM亚群和 TRM在不同组织中的转录和代谢特征已经开始出现 聚焦。TRM是局部可移动的，巡视组织寻找抗原，并可在 抗原重新暴露，但不再进入血液，都是血基所不能及 学习。值得注意的是，对人类抗原特异性TRM的研究很少，因此对 总体而言，TRM人群可能会忽视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。目标1专注于VZV的内源性再激活并使用活组织检查 治愈的带状疱疹和对照皮肤，第一次充分描述了有帮助的人类 单细胞水平的病毒特异性TRM。AIM 2使用新型RZV疫苗治疗带状疱疹 预防，即使在老年人中仍然有效，以确定疫苗是否导致 为了在皮肤中种植TRM，改善了体内归巢承诺的细胞池 血，或者两者兼而有之。综上所述，这些研究将增加我们对年龄的理解- 生命效应器T细胞的相关变化和可能有用的克服策略 免疫衰老。