Pathogenic and Protective T Cells in Toxoplasmosis

弓形虫病中的致病性和保护性 T 细胞

• 批准号: 7931239
• 负责人: George S. Yap
• 金额: $ 39万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-26 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7931239
• 关键词: Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Antigens; Automobile Driving; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Differentiation process; Cell Lineage; Cells; Collaborations; Communicable Diseases; Costs and Benefits; Cytokine Signaling; Disease; Epitopes; Equilibrium; Feedback; Generations; Goals; Human; Immediate Recalls; Immune; Immune response; Immunity; Immunization; Immunologic Deficiency Syndromes; Infection; Infectious Agent; Inflammatory; Inflammatory Response; Interleukin-10; Interleukin-12; Investigation; Kinetics; Knockout Mice; Laboratories; Mediating; Memory; Molecular; Morbidity - disease rate; Mus; Parasites; Pathology; Phenotype; Population; Process; Production; Protozoa; Publishing; Reagent; Regulation; Role; Signal Transduction; Source; System; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Th1 Cells; Tissues; Toxoplasma gondii; Toxoplasmosis; Transgenic Mice; Transgenic Organisms; Uracil; Vaccination; Vaccines; antimicrobial; autocrine; cytokine; granzyme B; immunopathology; insight; microbial; mortality; mouse model; novel; paracrine; pathogen; prevent; programs; response; vaccination strategy

A successful cellular immune response to Toxoplasma gondii and many other intracellular pathogens involves a delicate balance between the actions of IL-12, a proinflammatory innate cytokine triggered by the parasite and IL-10, a regulatory cytokine produced by adaptive T cells to prevent immunopathology. The overall goal of this proposal is to explore how IL-12 controls the generation and persistence of parasitereactive CD8 effector and memory cells required for protective immunity and how IL-10 acts in a novel autocrine fashion to avert tissue damage. Using a new mouse model with T-cell lineage specific interference in IL-10 signaling, we have obtained evidence that IL- 10 activation of a T-cell intrinsic anti-inflammatory response is required to prevent morbidity and mortality during T. gondii infection. We will use this transgenic and other knockout mouse models to elucidate the kinetics, regulation and functional consequences of IL-10 responsiveness during the Th1 response to T. gondii and explore a novel mechanism for how IL-10 cell-autonomously restrains Th1 cytokine responses. We have recently described four subpopulations of CD8 cells induced by immunization with the cps-vaccine strain of T. gondii and have published evidence that IL-12 is critically required for the generation of effector CD8 T cells expressing IFNγ, granzyme B and KLRG1. In collaboration with Dr. Hidde Ploegh¿s laboratory at MIT, we have identified the first Kb-restricted CTL epitope from T. gondii and our collaborators have also developed a cloned mouse line bearing monoclonal na¿ve CD8 T cells reactive to this Kbrestricted T. gondii antigen. Using these new mouse and immunological reagents, we will elucidate the cytokine requirements, lineage relationships and functional significance of the heterogenous CD8 T cell subsets induced by T. gondii vaccination and infection. We will critically assess the costs and benefits of IL-12 signaling on the immediate and recall CD8 protective response to re-infection.

对弓形虫和许多​​其他弓形虫的成功细胞免疫反应 细胞内病原体涉及 IL-12 的作用之间的微妙平衡，IL-12 是一种促炎剂。 由寄生虫和调节性细胞因子 IL-10 触发的先天细胞因子 由适应性 T 细胞产生以预防免疫病理学。本次活动的总体目标 该提案旨在探索 IL-12 如何控制寄生虫反应性的产生和持续 保护性免疫所需的 CD8 效应细胞和记忆细胞以及 IL-10 的作用 以一种新颖的自分泌方式发挥作用，以避免组织损伤。使用新的鼠标模型 T 细胞谱系特异性干扰 IL-10 信号传导，我们已获得证据表明 IL- 10 需要激活 T 细胞内在抗炎反应来预防 弓形虫感染期间的发病率和死亡率。我们将使用这种转基因和其他 敲除小鼠模型以阐明动力学、调节和功能后果 在对弓形虫的 Th1 反应过程中 IL-10 反应性的变化，并探索一种新的方法 IL-10 细胞如何自主抑制 Th1 细胞因子反应的机制。我们有 最近描述了通过免疫接种诱导的四种 CD8 细胞亚群 弓形虫的 cps 疫苗株，并已发表证据表明 IL-12 对弓形虫至关重要 产生表达 IFNγ、颗粒酶 B 和的效应 CD8 T 细胞所需 KLRG1。通过与麻省理工学院 Hidde Ploegh 博士的实验室合作，我们发现 来自弓形虫的第一个 Kb 限制性 CTL 表位，我们的合作者还 开发了一种克隆小鼠系，其含有对此 Kbrestricted 具有反应性的单克隆幼稚 CD8 T 细胞 弓形虫抗原。使用这些新的小鼠和免疫试剂，我们将 阐明细胞因子的需求、谱系关系和功能意义 弓形虫疫苗接种和感染诱导的异质 CD8 T 细胞亚群。我们 将严格评估 IL-12 信号传导的即时和召回的成本和效益 CD8 对再次感染的保护性反应。