Molecular Determinants of Tissue-resident Memory T cell Fate in Acute and Chronic Infection

急性和慢性感染中组织驻留记忆 T 细胞命运的分子决定因素

• 批准号: 10214451
• 负责人: Ananda W Goldrath
• 金额: $ 194.89万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-17 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214451
• 关键词: Algorithms; Antigens; Automobile Driving; Bioinformatics; Blood; Body Surface; CD8-Positive T-Lymphocytes; Cause of Death; Cell Differentiation process; Cells; Chronic; Communicable Diseases; Computational Biology; Computer Analysis; Data; Data Set; Dependence; Development; Disease; Disease Outcome; Epigenetic Process; Gene Expression; Gene Expression Profiling; Generations; Genetic Transcription; Genital; Genitalia; Genomics; Goals; Growth; Health; Heterogeneity; Homeostasis; Host Defense; Human; Immune; Immunity; Immunologic Memory; Infection; Inhibitor of Differentiation Proteins; Intestines; Knowledge; Laboratories; Lymphocyte; Lymphoid Tissue; Maintenance; Malignant Neoplasms; Mediating; Memory; Molecular; Morbidity - disease rate; Neoplasm Metastasis; Pathway interactions; Phase; Population; Process; Regulatory Element; Respiratory Mucosa; Role; Sentinel; Site; Skin; T cell differentiation; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; Vaccination; Virus Diseases; Vital capacity; acute infection; adaptive immunity; cell fate specification; chronic infection; design; exhaust; exhaustion; first responder; global health; immunopathology; improved; intestinal epithelium; metaplastic cell transformation; mortality; novel; novel strategies; novel vaccines; pathogen; programs; recruit; response; single cell analysis; single cell sequencing; tool; transcription factor; transcriptomics; tumor growth; vaccine development

OVERALL SUMMARY: Mortality from infectious diseases remains the second leading cause of death worldwide; a further toll on human health is exacted by disease-associated morbidity. The development of new vaccines is, therefore, an important priority for improving global health. Immunological memory is a cardinal feature of adaptive immunity and its induction is the underlying goal of vaccination. Long-lived memory T cells mediate protection from reinfection with previously encountered pathogens; keep chronic, opportunistic and latent pathogens at bay; and can serve as endogenous defenders against tumor growth and metastases. The memory T cell population is heterogeneous, typically categorized into central memory cells found in the blood and lymphoid tissues, or effector memory cells predominantly located in the blood and non-lymphoid tissues. The recent recognition of a third subset of memory lymphocytes, termed tissue-resident memory cells (Trm), that reside strictly within tissues and do not recirculate requires a revision of our understanding of memory T cell differentiation. Tissue- resident T cells provide essential sentinel protection at body surfaces such as the intestinal epithelium, and, are now clearly understood to be among the key `first responders' in many infection settings. Although we now know that resident-memory cells are an essential component of immune memory, little is known about the transcriptional pathways regulating their formation, survival and function. Improving our understanding of these topics will allow us to harness the immediate protective capacity of this vital memory T cell population and modulate activity in the context of immunopathology. To this end, we propose three synergistic projects that all leverage novel single-cell, genomic and computational analyses provided by two Cores to: 1) Define the unanticipated roles of key transcription factors in Trm formation and identify novel molecular determinants of Trm differentiation and homeostasis; 2) Identify early molecular regulators of Trm cell fate specification within different tissues in the context of acute and chronic infections using single-cell analyses of gene expression and computational approaches; 3) Define exhausted Trm during chronic viral infection and identify core regulators that determine their accumulation and hypo-functional state. Understanding the generation and homeostasis of tissue-resident memory cells will allow the exploitation of the immediate protective capacity of this vital memory population and provide strategies to modulate this activity in the context of immunopathology. We have assembled a team of five laboratories, which together possess the tools and expertise to resolve the transcriptional network driving memory T cell formation and exploit this knowledge to realize advances in regulating immunity in tissues. !

OVERALL SUMMARY: 传染病造成的死亡仍然是全球第二大死亡原因； a further toll on 人类健康受到疾病相关发病率的影响。因此，新疫苗的开发是一个 改善全球健康的重要优先事项。免疫记忆是适应性免疫的主要特征 其诱导是疫苗接种的根本目标。长寿命记忆 T 细胞介导保护 先前遇到的病原体再次感染；阻止慢性、机会性和潜在病原体； 并可以作为对抗肿瘤生长和转移的内源性防御者。记忆T细胞群 是异质的，通常分为血液和淋巴组织中发现的中央记忆细胞，或者 效应记忆细胞主要位于血液和非淋巴组织中。最近认可了一个 记忆淋巴细胞的第三个子集，称为组织驻留记忆细胞（Trm），严格驻留在组织内 组织并且不进行再循环，这需要我们修改对记忆 T 细胞分化的理解。组织- 常驻 T 细胞在肠上皮等身体表面提供重要的哨兵保护，并且， 现在人们清楚地知道他们是许多感染环境中关键的“第一反应者”。 Although we now 尽管知道常驻记忆细胞是免疫记忆的重要组成部分，但人们对它知之甚少。 调节其形成、存活和功能的转录途径。 提高我们对这些主题的理解将使我们能够利用这一点的直接保护能力 重要的记忆 T 细胞群体并在免疫病理学背景下调节活性。为此，我们 提出三个协同项目，全部利用新颖的单细胞、基因组和计算分析 由两个核心提供： 1) 定义关键转录因子在 Trm 形成中的意外作用和 确定 Trm 分化和稳态的新分子决定因素； 2) 识别早期分子 急性和慢性感染背景下不同组织内 Trm 细胞命运规范的调节因子 使用基因表达的单细胞分析和计算方法； 3) 定义期间的耗尽Trm 慢性病毒感染并确定决定其积累和功能低下状态的核心调节因子。 了解组织驻留记忆细胞的生成和稳态将允许利用 这种重要记忆群体的即时保护能力，并提供调节这种活动的策略 免疫病理学的背景。我们组建了一个由五个实验室组成的团队，这些实验室共同拥有 解决驱动记忆 T 细胞形成的转录网络并利用该网络的工具和专业知识 知识以实现组织免疫调节方面的进步。 ！