Pathogenic and Protective T cells in Toxoplasmosis

描述（由申请人提供）：对弓形虫和许多其他细胞内病原体的成功细胞免疫应答涉及IL-12和IL-10之间的微妙平衡，IL-12是寄生虫触发的促炎性先天细胞因子，IL-10是适应性T细胞产生的调节细胞因子，用于预防免疫病理。本提案的总体目标是探索IL-12如何控制保护性免疫所需的寄生虫反应性CD8效应细胞和记忆细胞的产生和持续，以及IL-10如何以一种新的自分泌方式起作用以避免组织损伤。利用一种t细胞谱系特异性干扰IL-10信号传导的新小鼠模型，我们已经获得证据表明，IL-10激活t细胞内在抗炎反应是预防弓形虫感染期间发病和死亡所必需的。我们将使用这种转基因和其他敲除小鼠模型来阐明Th1对弓形虫反应过程中IL-10反应的动力学、调节和功能后果，并探索IL-10细胞如何自主抑制Th1细胞因子反应的新机制。我们最近描述了四个由弓形虫cps疫苗株免疫诱导的CD8细胞亚群，并发表证据表明IL-12对于产生表达IFN3、颗粒酶B和KLRG1的效应CD8 T细胞至关重要。与麻省理工学院Hidde Ploegh博士的实验室合作，我们已经从弓形虫中确定了第一个Kb限制性CTL表位，我们的合作者还开发了一种克隆小鼠系，其单克隆nave CD8 T细胞对这种Kb限制性弓形虫抗原有反应。利用这些新的小鼠和免疫试剂，我们将阐明弓形虫接种和感染诱导的异质CD8 T细胞亚群的细胞因子需求、谱系关系和功能意义。我们将严格评估IL-12信号对再次感染的即时和召回CD8保护性反应的成本和收益。

DESCRIPTION (provided by applicant): A successful cellular immune response to Toxoplasma gondii and many other intracellular pathogens involves a delicate balance between the actions of IL-12, a pro- inflammatory 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 parasite- reactive 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 IFN3, 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 naove CD8 T cells reactive to this Kb- restricted 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. PUBLIC HEALTH RELEVANCE: Disease caused by parasitic protozoa and other intracellular microbial agents are major causes of mortality and morbidity worldwide. Morbidity and mortality may be caused by immunodeficiency leading to tissue destruction by the parasites or these may result from an overzealous or dysregulated immune response. The studies proposed here will provide new insights into how potentially pathogenic Th1 cells are restrained and how protective CD8 T cells are generated and maintained over the long term, specifically with respect to how cytokines control these immune processes. Insights from these investigations may become useful for vaccination strategies and the management of inflammatory and infectious diseases.