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

总体总结： 传染病死亡率仍然是世界范围内第二大死亡原因; 人类健康是由疾病引起的发病率决定的。因此，新疫苗的开发是一项 改善全球健康的重要优先事项。免疫记忆是适应性免疫的一个重要特征 并且其诱导是疫苗接种的根本目标。长寿命记忆T细胞介导的保护， 再次感染以前遇到的病原体;防止慢性、机会性和潜伏病原体; 并且可以作为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，通常分类为血液和淋巴组织中发现的中央记忆细胞，或 效应记忆细胞主要位于血液和非淋巴组织中。最近，A 记忆淋巴细胞的第三个子集，称为组织驻留记忆细胞（Trm），严格居住在 组织和不再循环需要我们的记忆T细胞分化的理解修订。组织- 驻留T细胞在体表如肠上皮提供必需的前哨保护，并且， 现已清楚地认识到，在许多感染情况下，这些人是关键的“第一反应者”。尽管我们现在 虽然我们知道驻留记忆细胞是免疫记忆的重要组成部分，但对它们的作用却知之甚少。 转录途径调节它们的形成、存活和功能。 提高我们对这些主题的理解将使我们能够利用这种直接的保护能力， 在免疫病理学的背景下，重要的记忆T细胞群和调节活性。为此我们 我提出了三个协同项目，都利用新的单细胞，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， 鉴定Trm分化和稳态新分子决定因素; 2）鉴定早期分子 急性和慢性感染背景下不同组织中Trm细胞命运特化的调节因子 使用基因表达的单细胞分析和计算方法; 3）在 慢性病毒感染，并确定决定其积累和功能减退状态的核心调节因子。 了解组织驻留记忆细胞的产生和稳态将允许利用组织驻留记忆细胞。 立即保护能力，并提供策略来调节这种活动， 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，他们共同拥有 工具和专业知识来解决驱动记忆T细胞形成的转录网络，并利用这一点 知识，以实现在调节免疫组织的进展。!

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. !