Biology of human cytotoxic CD4 T cells (CD4-CTLs) in viral infections

病毒感染中人类细胞毒性 CD4 T 细胞 (CD4-CTL) 的生物学

• 批准号: 10580761
• 负责人: Pandurangan Vijayanand
• 金额: $ 69.81万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-11 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10580761
• 关键词: Biology; human; cytotoxic; CD4; cells

PROJECT SUMMARY Project 3 The existence of MHC class II-restricted CD4+ helper T cells with cytotoxic potential (CD4-CTLs) has been reported in humans with several viral infections. Importantly, the CD4-CTLs have been reported to play a protective role in several of these viral infections. However, little is known in humans about the biology of CD4- CTL generation and their functional properties. We recently performed single-cell RNA-seq in over 9000 cells to unravel CD4-CTL heterogeneity and functional properties. Our analysis led to the discovery of a distinct subset of long-lived CD4-CTL memory precursors. Understanding the biology of such long-lived CD4-CTL precursors will pave the way for developing strategies to boost durable CD4-CTL immune responses following vaccination against infections. In Project 3, specific aim 1, we will determine the phenotype and functional properties of pathogen-specific and tissue-specific CD4-CTLs in humans. (A) Pathogen-specific features of CD4-CTLs: We will compare the phenotype and molecular features of circulating DENV-, hCMV-, EBV-reactive CD4-CTL precursors and effector cells. (B) Tissue-specific features of CD4-CTLs: Here, we will compare hCMV-, EBV- and pertussis vaccine-reactive CD4-CTLs present in human lungs to those circulating in the blood. In addition, we will compare pathogen-specific CD4-CTLs present in tonsil (lymphoid) tissue vs. blood (collaboration with Crotty, Project 1). (C) Vaccine-induced CD4-CTLs: In collaboration with Crotty (Project 1), we will determine whether yellow fever vaccination induces the generation of CD4-CTL precursors in the blood and lymph nodes. In specific aim 2, (A) we will identify molecular transcription factors driving CD4-CTL differentiation and (B) test their function in in vivo models and in human cells. In summary, our work will fundamentally advance our understanding of the molecular basis of CD4-CTL immunity in humans and will benefit from the synergistic interactions with other Projects.

项目摘要 项目3 具有细胞毒性电位（CD4-CTL）的MHC II限制CD4+辅助T细胞的存在一直是 在患有几种病毒感染的人类中报道。重要的是，据报道CD4-CTL播放 这些病毒感染中的几种保护作用。但是，在人类中，关于CD4-的生物学知之甚少 CTL生成及其功能性能。我们最近在9000多个细胞中进行了单细胞RNA-seq 阐明CD4-CTL异质性和功能特性。我们的分析导致发现了一个独特的 长寿命CD4-CTL存储前体的子集。了解如此长寿命的CD4-CTL的生物学 前体将为制定策略铺平道路，以提高耐用的CD4-CTL免疫反应 针对感染的疫苗接种。在项目3（特定目标1）中，我们将确定表型和功能 人类病原体特异性和组织特异性CD4-CTL的特性。 （a）特定于病原体的特征 CD4-CTL：我们将比较循环DENV-，HCMV-，EBV反应的表型和分子特征 CD4-CTL前体和效应细胞。 （b）CD4-CTL的组织特异性特征：在这里，我们将比较 HCMV-，EBV和百日咳疫苗反应性CD4-CTL在人肺中存在于循环的人中 血。此外，我们将比较扁桃体（淋巴）组织中存在的病原体特异性CD4-CTL与血液 （与Crotty合作，项目1）。 （c）疫苗诱导的CD4-CTL：与Crotty（项目1）合作 我们将确定黄热病疫苗接种是否诱导血液中CD4-CTL前体的产生 和淋巴结。在特定目标2中，（a）我们将确定驱动CD4-CTL的分子转录因子 分化和（b）在体内模型和人类细胞中测试其功能。总而言之，我们的工作将 从根本上促进我们对人类CD4-CTL免疫的分子基础的理解，并将 从与其他项目的协同互动中受益。