MEMORY CD8+T CELLS IN PROTECIVE IMMUNITY TO MALARIA

由孢子虫疟原虫（Plasmodia sporozoite, 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病间歇性发作，一旦接触停止就会迅速消退。相比之下，用辐照（γ） spz对人类和实验室啮齿动物进行免疫，结果是无菌和持久的保护。由于γ -spz发生部分分裂，肝脏成为诱导和维持保护性免疫所需的疟原虫抗原的主要储存库。保护机制包括Ig、CD4+T细胞，特别是靶向感染肝细胞并释放inf - γ以消除寄生虫的效应CD8+ T细胞。然而，持续保护的机制和肝脏作为免疫器官在促进长期免疫中的作用仍不清楚。因此，本提案的总体目标是确定记忆性CD8+ T细胞是否介导持久保护，并了解肝脏在这一过程中的参与。CD8+ T细胞不断进入肝脏，成为哨兵短命效应T细胞，可以维持保护作用。相反，根据我们的观察，记忆性CD8+ CD44hiCD45RBlo T细胞存在于长期免疫小鼠的肝脏中，我们的假设是肝脏记忆性CD8+ T细胞发挥保护作用。为了验证这一假设，我们提出了实验来检验(1)来自长期和短期保护小鼠的CD8+ T细胞是否可以通过激活/记忆标记、功能特性和凋亡来区分；(2)记忆性CD8+ T细胞存在于未形成长期保护的小鼠体内；(3)记忆性CD8+T细胞的维持需要APC、细胞因子、CD4+ T和NK T细胞。γ -spz诱导的保护性免疫模型的结果为目前开发抗疟疾疫苗的战略奠定了基础，这一战略的改进有待于对长期保护性免疫背后的细胞记忆反应的理解。

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.