Protective CD4+ T Cells

项目摘要/摘要 因获得性或原发免疫缺陷而缺乏CD4T细胞的人通常会因感染而患病 与分枝杆菌、沙门氏菌和隐球菌等在吞噬小体中持续存在的微生物 吞噬细胞。吞噬病原体通常由肉芽肿中产生干扰素-γ的Th1细胞控制 在最初的感染部位形成。然而，由于未知的原因，Th1细胞不能清除微生物 是肉芽肿造成的。允许Th1细胞控制肉芽肿感染的调节机制 如果不消除它们，就不能被理解。这一知识鸿沟阻碍了有效的发展 现在困扰着数十亿人的吞噬病原体疫苗。 该项目的目标是通过使用最先进的细胞跟踪和小鼠遗传技术来缩小这一差距 Th1细胞对典型吞噬病原体肠炎沙门氏菌多肽的特异性研究 并在感染过程中形成相关的肉芽肿。我们将建立在我们发现肠链球菌感染的基础上 通过测试以下观点推动两种表达不同趋化因子受体的Th1细胞的形成 持续感染和胸腺产生新的T细胞驱动了一个Th1群体产生Th1的循环 另一种是衰老和细胞毒性的。我们将使用荧光细菌来确定这些Th1 种群杀死吞噬细胞中的细菌或杀死携带细菌的吞噬细胞。我们还将 确定这些过程是否发生在巨噬细胞丰富的肉芽肿中，以及Th1细胞在其中扮演什么角色 通过操纵Th1细胞和肉芽肿巨噬细胞形成肉芽肿。潜在的回报来自 这个项目是对这种不寻常形式的非灭菌微生物控制的理解，这种控制可以保护 来自一些最致命病原体的具有免疫能力的人，但不可能通过 接种疫苗。

Project Summary/Abstract People lacking CD4+ T cells due to acquired or primary immunodeficiency usually become ill due to infection with microbes such as Mycobacteria, Salmonella, and Cryptococcus that persist in the phagosomes of phagocytes. Phagosomal pathogens are normally controlled by IFN-γ-producing Th1 cells in granulomas that form at the initial site of infection. For unknown reasons, however, the Th1 cells can not eliminate the microbes from the granulomas. The regulatory mechanisms that allow Th1 cells to control these infections in granulomas without eliminating them are not understood. This knowledge gap has prevented the development of effective vaccines for phagosomal pathogens that now afflict billions of people. The goal of this project is to close this gap by using state of the art cell tracking and mouse genetic techniques to study how Th1 cells specific for peptides from the prototypical phagosomal pathogen Salmonella enterica and associated granulomas develop during infection. We will build on our finding that S. enterica infection drives the formation of two types of Th1 cells expressing different chemokine receptors by testing the idea that persistent infection and thymic production of new T cells drives a cycle in which one Th1 population generates the senescent and cytotoxic other one. We will use fluorescent bacteria to determine whether these Th1 populations kill the bacteria in phagocytes or kill the phagocytes that harbor the bacteria. We will also determine whether these processes occur in macrophage-rich granulomas and what role Th1 cells play in granuloma formation by manipulating the Th1 cells and granuloma macrophages. The potential payoff from this project is an understanding of this unusual form of non-sterilizing microbial control that protects immunocompetent individuals from some of the deadliest pathogens but has been impossible to harness via vaccination.