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

项目摘要 CD 8 T细胞防御肿瘤和细胞内病原体。经典的免疫监视模式 假设大多数CD 8 T细胞通过不断地在血液、组织和淋巴中循环来检测感染。 在最近发现大部分记忆性CD 8 T细胞在淋巴细胞中的表达后，这一观点被显著修正。 屏障粘膜器官不进行常规循环。后一组细胞，称为常驻记忆T细胞（TRM）， 已经显示对于控制靶向粘膜器官如女性的感染特别关键 生殖道（FRT）。作为屏障组织，FRT是许多难治性病原体的常见靶标，包括 HIV和单纯疱疹病毒。越来越多的人一致认为，针对这些疾病的疫苗应该努力 以产生抗体以及T细胞介导的应答。因此，增加抗病毒T细胞 生殖粘膜中的密度是T细胞疫苗学领域中的关键驱动因素。成功在这些 尝试将依赖于对粘膜TRM生物学的完全理解。我们假设维持 粘膜中丰富的功能性TRM取决于TRM成功适应局部粘膜 环境;一个不太了解的过程。局部组织衍生因子被认为是关键的调节因子 这些目标是可以调整的，以影响这一进程的数量、质量和 TRM的分布我们计划探索FRT CD 8 TRM的粘膜适应程序的两个关键方面。下 第一个目标，我们将在不同阶段对T细胞进行转录和表观遗传分析，因为它进入了细胞周期。 FRT并分化为成熟的TRM细胞。我们的表型特征揭示了一个显著的 TRM群体之间的异质性以及单个细胞中的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群体的分化轨迹， 控制这个过程的分子调节器。在第二个目标下，我们将审问具有 参与抗病毒CD 8 TRM的建立、分化和功能。我们的飞行员数据显示 局部性类固醇和转化生长因子-β（TGF-β）参与FRT TRM分化， 功能了解FRT CD 8 TRM分化和功能的分子基础 调节将揭示关键的目标，可用于改善CD 8 T细胞的数量和质量， 生殖粘膜用于接种。

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.