Project 1 - Local regulation of T cell differentiation and function in the reproductive mucosa

项目总结 CD8 T细胞可抵御肿瘤和细胞内病原体。经典的免疫监测范式 假设大多数CD8T细胞通过不断在血液、组织和淋巴中循环来检测感染。 这一观点在最近发现很大一部分记忆性CD8T细胞在 屏障粘膜器官不是常规的循环。后一组细胞被称为驻留记忆T细胞(TRM)， 已被证明对控制针对像女性这样的粘膜器官的感染特别关键 生殖道(FRT)。作为一种屏障组织，FRT经常成为许多难治性病原体的目标，包括 艾滋病毒和单纯疱疹病毒。越来越多的人达成共识，认为针对这些疾病的疫苗应该努力 既能产生抗体又能产生T细胞介导的反应。因此，努力增加抗病毒T细胞 在T细胞疫苗领域，生殖粘膜的密度一直是一个关键的驱动因素。在这些方面取得成功 这些尝试将取决于对粘膜TRM生物学的全面了解。我们假设维持 粘膜中丰富的功能TRM是基于TRM对局部粘膜的成功适应 环境；一个鲜为人知的过程。局部组织衍生因子被认为是关键的调节器 并代表可以调节的重要目标，以影响数量、质量和 TRM的分布。我们计划探索FRT CD8 TRM粘膜适应计划的两个关键方面。在……下面 第一个目标是，我们将在T细胞进入不同阶段时对其进行转录和表观遗传学分析 FRT并分化为成熟的TRM细胞。我们的表型特征揭示了一个重要的 单株TRM种群间的异质性及其转录和染色质景观分析 细胞分辨率将使我们能够更深入地了解这些种群的分化轨迹，并 控制这一过程的分子调节器。在第二个目标下，我们将询问具有 参与了抗病毒CD8TRM的建立、分化和功能。我们的飞行员数据显示 局部性激素和转化生长因子-β在FRT-TRM分化和分化中的作用 功能。了解FRT CD8 TRM分化和功能的分子基础 调控将揭示可以利用的关键靶点，以提高CD8 T细胞的数量和质量 用于接种的生殖黏膜。

PROJECT SUMMARY CD8 T cells defend against tumors and intracellular pathogens. The classical immunosurveillance paradigm assumes that most CD8 T cells survey for infections by constantly circulating through blood, tissues, and lymph. This view is being significantly revised after the recent discovery that a large fraction of memory CD8 T cells in barrier mucosal organs do not routinely circulate. This later group of cells, named resident memory T cells (TRM), have shown to be particularly critical for controlling infections that target mucosal organs like the female reproductive tract (FRT). As a barrier tissue FRT is a frequent target of number of intractable pathogens including HIV and Herpes Simplex virus. There is a growing consensus that vaccines against these diseases should strive to generate both antibody as well as T-cell mediated responses. And as such efforts to increase antiviral T cell density in reproductive mucosae has been a key driving factor in the field of T cell vaccinology. Success in these attempts will depend on a complete understanding of mucosal TRM biology. We hypothesize that maintaining abundant functional TRM in the mucosae is predicated on TRM’s successful adaptation to the local mucosal environment; a process that is poorly understood. Local tissue-derived factors are thought to be critical regulators of this process and represent important targets that can be modulated to influence the quantity, quality and distribution of TRM. We plan to explore two key aspects of mucosal adaptation program of FRT CD8 TRM. Under the first aim, we will perform transcriptional and epigenetic analysis of T cells at distinct stages as it enters the FRT and differentiate into mature TRM cells. Our phenotypic characterization has revealed a significant heterogeneity among the TRM populations and the transcriptional and chromatin landscape analysis at single cell resolution will allow us to gain deeper insights into the differentiation trajectories of these populations and molecular regulators that control this process. Under the second aim, we will interrogate molecules that have been implicated in antiviral CD8 TRM establishment, differentiation and function. Our pilot data indicates involvement of local sex steroids and transforming growth factor-beta (TGF-b) in FRT TRM differentiation and function. Understanding the molecular underpinnings of how FRT CD8 TRM differentiation and function are regulated will reveal critical targets that can be exploited to both improve CD8 T cell quantity and quality in the reproductive mucosa for vaccination.