Regulation of Type1 Immunity to Toxoplasma

描述(申请人提供)：弓形虫是人和动物的一种主要的机会性寄生虫。疾病可能是由于弱的免疫反应导致宿主组织的寄生虫溶解，也可能是不适当或过度活跃的免疫反应引起的。对弓形虫和其他细胞内病原体的主要保护性免疫机制是由辅助性T细胞1(Th1)细胞介导的，Th1细胞产生促炎细胞因子干扰素-γ和肿瘤坏死因子-α。然而，当这些保护性细胞因子产生过多时，就会变成病理性的。Th1细胞是如何自我调节的还不是很清楚。我们在前一个资金阶段的工作已经揭开了Th1反应中的一个关键的负面控制环路，在这个环路中，干扰素-γ诱导抗炎细胞因子IL-10的产生，Th1细胞本身。因此，目前的应用将决定IL-10是如何调节的，以及如何保护宿主免受自身造成的免疫损伤。我们的第一个目标是首先确定是什么信号和细胞编程Th1细胞产生IL-10。其次，我们将研究特化的天然细胞在驱动产生IL-10的Th1细胞分化中的作用。最后，我们将阐明负反馈回路中的细胞因子和细胞成分，通过该回路，干扰素-γ诱导Th1记忆细胞中IL-10的重新激活。这些研究将确定免疫系统用来同时清除微生物病原体但也防止宿主组织损伤的关键机制。公共卫生相关性：由寄生虫、原虫和其他类型的细胞内病原体引起的人类疾病是全球人类死亡和发病的主要原因。疾病可能是由寄生虫破坏组织引起的，也可能是由于免疫反应过度引起的。这里提出的研究将促进对Th1反应如何提供对寄生虫和其他病原体的保护，以及防止或避免附带组织损伤的理解。这项研究获得的见解有望对慢性传染病的管理策略和治疗有所帮助。

DESCRIPTION (provided by applicant): Toxoplasma gondii is a major opportunistic parasitic infectious agent in man and animals. Disease can result from a weak immune response resulting in parasite lysis of host tissue or it can ensue from an inappropriate or overly exuberant immune reaction. The major protective immune mechanism against T. gondii and other intracellular pathogens is that mediated by T helper 1 (Th1) cells, which produce pro-inflammatory cytokines, IFN-gamma and TNF-alpha. Nevertheless, when produced in excess, these protective cytokines can become pathologic. How Th1 cells are self-regulated has not been well understood. Our work from the previous funding period has unraveled a key negative control loop in Th1 responses whereby IFN-gamma induces the production of the anti-inflammatory cytokine IL-10, Th1 cells themselves. Therefore, the current application will determine how IL-10 is regulated and functions to protect the host from self-inflicted immune-injury. Our first aim is to determine what signals and cells program the Th1 cells to produce IL-10 in the first place. Secondly, we will investigate the role of specialized innate cells in driving the differentiation of Th1 cells producing IL-10. Finally, we will elucidate the cytokine and cellular components of the negative feedback loop whereby IFN-gamma induces reactivation of IL-10 in Th1 memory cells. These studies will identify key mechanisms used by the immune system to simultaneously clear microbial pathogens but also prevent host tissue damage. PUBLIC HEALTH RELEVANCE: Human diseases caused parasitic protozoa and other types of intracellular pathogens are major causes of human mortality and morbidity globally. Disease may be caused by tissue destruction by parasites or result from an over-reaction by the immune response. The studies proposed here will advance understanding of how the Th1 response can provide protection against parasites and other pathogens but also prevent or avert collateral tissue damage. Insights obtained from this research will hopefully be useful for management strategies and treatment for chronic infectious diseases.