Pathogenic and Protective T Cells in Toxoplasmosis

成功的弓形虫等多种细胞免疫应答 细胞内病原体涉及IL-12、促炎因子、 寄生虫和调节细胞因子IL-10触发的先天细胞因子 由适应性T细胞产生，以防止免疫病理。这个项目的总体目标是 建议探索IL-12如何控制副反应性细胞的产生和持续 保护性免疫所需的CD8效应和记忆细胞以及IL-10如何 以一种新颖的自分泌方式发挥作用，避免组织损伤。将新的鼠标模型与 T细胞系对IL-10信号的特异性干扰，我们获得了IL-10信号传导的证据。 10需要激活T细胞的内在抗炎反应以防止 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 基因敲除小鼠模型以阐明动力学、调节和功能后果 研究弓形虫Th1应答过程中IL-10的反应，并探索一种新的 IL-10细胞自主抑制Th1细胞因子反应的机制。我们有 最近描述了由免疫诱导的四个CD8细胞亚群 弓形虫CPS疫苗株，并已发表证据表明IL-12对 产生表达干扰素、颗粒酶B和干扰素的效应性CD8T细胞 KLRG1.通过与麻省理工学院S实验室的希德·普洛夫博士合作，我们发现 弓形虫及其合作者的第一个Kb限制性CTL表位也 建立了克隆的小鼠株系，其克隆的CD8T细胞可与该病毒发生反应 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源CD8T细胞亚群。我们 将严格评估IL-12信号在即时和召回中的成本和收益 CD8对再次感染的保护性反应。

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.