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

项目总结 项目3 具有细胞毒潜能的MHC-II类限制性CD4+辅助性T细胞(CD4-CTL)的存在已被 据报道，在患有几种病毒感染的人类中。重要的是，据报道，cd4-ctl在 在其中几种病毒感染中起到保护作用。然而，人类对CD4的生物学知之甚少。 CTL的产生及其功能特性。我们最近在9000多个细胞中进行了单细胞rna-seq。 了解CD4-CTL的异质性和功能特性。我们的分析导致发现了一种独特的 长寿的CD4-CTL记忆前体的子集。了解这种长寿的CD4-CTL的生物学 前体将为制定策略以增强下列持久的CD4-CTL免疫反应铺平道路 接种预防感染的疫苗。在项目3的具体目标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)病原体的具体特征 CD4-CTL：我们将比较循环中的DENV-、HCMV-、EBV-反应的表型和分子特征 CD4-CTL前体细胞和效应细胞。(B)CD4-CTL的组织特异性特征：在这里，我们将比较 人肺中存在的人巨细胞病毒、EB病毒和百日咳疫苗反应性CD4-CTL对循环中的 血。此外，我们还将比较扁桃体(淋巴)组织和血液中存在的病原体特异性CD4-CTL (与Crotty合作，项目1)。(C)疫苗诱导的CD4-CTL：与Crotty合作(项目1)， 我们将确定接种黄热病疫苗是否会诱导血液中产生CD4-CTL前体细胞 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 (B)在活体模型和人体细胞中测试它们的功能。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和意志 从与其他项目的协同互动中受益。

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.