Pathogenic and Protective T cells in Toxoplasmosis

描述（由申请人提供）：对刚地弓形虫和许多其它细胞内病原体的成功细胞免疫应答涉及IL-12（由寄生虫触发的促炎性先天性细胞因子）和IL-10（由适应性T细胞产生以防止免疫病理学的调节性细胞因子）的作用之间的微妙平衡。该提议的总体目标是探索IL-12如何控制保护性免疫所需的寄生虫反应性CD 8效应细胞和记忆细胞的产生和持续，以及IL-10如何以新的自分泌方式起作用以避免组织损伤。使用一种新的小鼠模型，T细胞谱系特异性干扰IL-10信号，我们已经获得的证据表明，IL- 10激活T细胞内在的抗炎反应是必要的，以防止发病率和死亡率在T。弓形虫感染我们将使用这种转基因和其他基因敲除小鼠模型来阐明IL-10反应性在Th 1应答T细胞过程中的动力学、调节和功能后果。探讨IL-10细胞自主抑制Th 1细胞因子应答的新机制。我们最近描述了四个亚群的CD 8细胞诱导免疫接种的CPS疫苗株T。并且已经发表的证据表明IL-12对于表达IFN 3、颗粒酶B和KLRG 1的效应CD 8 T细胞的产生是至关重要的。通过与麻省理工学院HiddePloegh博士实验室的合作，我们已经从T.弓形虫和我们的合作者还开发了一种克隆小鼠系，其携带对这种Kb-限制性T细胞反应的单克隆naove CD 8 T细胞。弓形虫抗原利用这些新的小鼠和免疫学试剂，我们将阐明T细胞诱导的异源性CD 8 T细胞亚群的细胞因子需求、谱系关系和功能意义。弓形虫疫苗接种和感染。我们将严格评估IL-12信号传导对再感染的即时和回忆CD 8保护性反应的成本和效益。 公共卫生相关性：由寄生原生动物和其他细胞内微生物剂引起的疾病是世界范围内死亡和发病的主要原因。发病和死亡可能是由免疫缺陷引起的，导致组织被寄生虫破坏，或者这些可能是由过度热心或失调的免疫反应引起的。本文提出的研究将为潜在致病性Th 1细胞如何受到抑制以及保护性CD 8 T细胞如何产生和长期维持提供新的见解，特别是关于细胞因子如何控制这些免疫过程。从这些调查的见解可能成为有用的疫苗接种策略和炎症和传染病的管理。

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.