Project 1 - Goldrath

摘要--项目1--Goldrath： 长期存活的记忆细胞提供保护，防止再次感染，并可以作为内源性防御者 肿瘤生长和转移。组织驻留记忆T细胞在体内提供必要的哨兵保护 表面，如肠道上皮，现在被清楚地理解为是关键的 在许多感染环境中的应答者。尽管我们知道驻留记忆细胞是必不可少的 免疫记忆的组成部分，对调节其形成的转录途径知之甚少， 生存和功能。 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，生命记忆T细胞群并调节它们的活动，这是 计划项目的总体目标。受益于尖端表观遗传学的综合专业知识 和基因组分析，CD8+T细胞生物学，以及项目和核心领导的慢性感染， 项目1将定义驱动独特记忆状态的转录程序之间的关系，重点是 常驻内存与循环内存。 涉及的异质性、基因表达程序、功能活性和调节元件- 将研究记忆细胞的发育，以产生对转录如何 Blimp1、Bcl6、T-bet和E/ID蛋白等调节蛋白驱动记忆中不同的分化程序 细胞前体促进不同记忆命运的分化。为此，具体而言，我们将：(1)界定 转录程序驱动独特记忆状态的关系，以理解驻留记忆 T细胞分化与循环记忆T细胞群不同。基因的单细胞分析 表达将与高通量功能筛选配对，以评估混合转录网络 调节Trm种群的形成和动态平衡。(二)破译社会矛盾依赖 Trm对拮抗转录抑制因子Blimp1和Bcl6在Trm分化和稳态中的作用。(3) 解析E蛋白转录因子及其调控因子在转录网络调控中的作用 组织驻留记忆T细胞在急慢性感染中的发育、功能和动态平衡 设置。我们的研究确定了控制驻留的关键分子决定因素和转录程序- 记忆T细胞命运规范对于指导下一代疫苗的合理设计至关重要 将特别旨在调用组织驻留记忆细胞介导的预防传染病和 恶毒。 好了！

SUMMARY-PROJECT 1-GOLDRATH: Long-lived memory cells provide protection from reinfection and can serve as endogenous defenders against tumor growth and metastases. Tissue-resident memory 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 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 their activity in the context of immunopathology, which is the overarching goal of the Program Project. Benefiting from the combined expertise in cutting-edge epigenetic and genomic analyses, CD8+ T cell biology, and chronic infection of the Program Project and Core Leaders, Project 1 will define the relationship of transcriptional programs driving unique memory states with a focus on resident versus circulating memory populations. The heterogeneity, gene-expression programs, functional activity and regulatory elements involved in resident- memory cell development will be studied to generate an integrated understanding of how transcriptional regulators such as Blimp1, Bcl6, T-bet, and E/Id proteins drive divergent differentiation programs in memory cell precursors to promote differentiation of distinct memory fates. To this end, specifically, we will: (1) Define the relationship of transcriptional programs driving unique memory states to understand how resident-memory T cell differentiation diverges from circulating memory T cell populations. Single-cell analysis of gene expression will be paired with high-throughput functional screening to assess the hybrid transcriptional network regulating the formation and homeostasis of Trm populations. (2) Decipher the contradictory dependence of Trm on the antagonistic transcriptional repressors, Blimp1 and Bcl6 in Trm differentiation and homeostasis. (3) Resolve the role of E protein transcription factors and their regulators in the transcriptional network governing the development, function and homeostasis of tissue-resident memory T cells in acute and chronic infectious settings. Our studies identifying key molecular determinants and transcriptional programs that control resident- memory T cell fate specification are critical to inform the rational design of the next generation of vaccines that will specifically aim to invoke tissue-resident memory cell-mediated protection from infectious diseases and malignancy. !