MEMORY CD8+T CELLS IN PROTECIVE IMMUNITY TO MALARIA

由疟原虫子孢子(SPZ)引起的疟疾是世界许多地区发病率和死亡率的主要原因。自然感染的保护使寄生虫血症出现间歇性发作，一旦暴露停止，寄生虫血症就会迅速消退。相比之下，用辐照(伽马)SPZ对人类和实验室啮齿动物进行免疫会产生无菌和持久的保护作用。由于伽玛-SPZ经历了部分分裂，肝脏成为诱导和维持保护性免疫所需的主要原虫抗原储存库。其保护机制包括免疫球蛋白、CD4T细胞，特别是以受感染的肝细胞为靶点的效应性CD8T细胞，并释放干扰素-γ以清除寄生虫。然而，持续保护的机制以及肝脏作为免疫器官在促进长期免疫方面的作用仍不清楚。因此，这项建议的总体目标是确定记忆CD8 T细胞是否介导了长期保护，并了解肝脏在这一过程中的参与。CD8 T细胞不断进入肝脏成为前哨短命效应T细胞，可以维持保护作用。相反，基于我们对长期免疫小鼠肝脏中存在记忆CD8 CD44hiCD45RBlo T细胞的观察，我们的假设是肝脏记忆CD8 T细胞起到保护作用。为了验证这一假设，拟议进行实验以检验(1)长期保护小鼠和短期保护小鼠的CD8 T细胞是否可以通过激活/记忆标记物、功能特性和细胞凋亡来区分；(2)记忆CD8 T细胞存在于不形成长期保护的小鼠中；(3)APC、细胞因子、CD4T和NK T细胞是维持记忆CD8 T细胞所必需的。伽马-SPZ诱导的保护性免疫模型的结果构成了目前开发抗疟疾疫苗的战略的基础，该疫苗的改进还有待于了解作为长期保护性免疫基础的细胞记忆反应。

Malaria, caused by Plasmodia sporozoites (spz) is a leading contributor to morbidity and mortality in many parts of the world. Protection by natural infection allows intermittent episodes of parasitemia to occur and decays rapidly once exposure ceases. By contrast, immunization of humans and laboratory rodents with irradiated (gamma) spz results in a sterile and long-lasting protection. Because gamma-spz undergo partial schizogony, the liver becomes a major depot of plasmodial antigens required for induction and maintenance of protective immunity. The mechanisms of protection include Ig, CD4+T cells, and particularly effector CD8+ T cells that target infected hepatocytes and release INF-gamma to eliminate the parasite. The mechanisms of sustained protection and the role of the liver as an immune organ in promoting long-term immunity, however, remain unknown. Therefore, the overall objective of this proposal is to determine whether memory CD8+ T cells mediate long-lasting protection and to understand the involvement of the liver in this process. CD8+ T cells that constantly ingress to the liver to become the sentinel short-lived effector T cells could maintain protection. Instead, based on our observations that memory CD8+ CD44hiCD45RBlo T cells are present in livers of long- term immune mice, our hypothesis is that liver memory CD8+ T cells play a role in protection. To test this hypothesis, experiments are propose to examine whether (1) CD8+ T cells from long- and short-term protected mice can be distinguished by activation/memory markers, functional properties, and apoptosis; (2) memory CD8+ T cells are present in mice that do not develop long-term protection; (3) APC, cytokines, CD4+ T and NK T cells are required for the maintenance of memory CD8+T cells. Results from models of protective immunity induced by gamma-spz have formed the basis for the current strategy to develop anti-malaria vaccines, the improvement of which awaits the understanding of cellular memory responses that underlie long-lasting protective immunity.