Regulation of Plasmodium-specific CD4+ T Cells

项目总结 疟原虫感染和疟疾仍然是全球卫生紧急情况。疟疾影响的不止是 去年有2亿人死亡，造成近60万人死亡。针对寄生虫的抗体反应对于 控制寄生虫复制和限制疟疾的严重程度。有效的抗体反应和最佳的 受刺激的B细胞需要来自CD4+T细胞的“帮助”。我们发表的研究表明，CD4+T细胞的功能是 在感染疟原虫后明显受损。我们将CD4+T细胞的功能降低与 诱导共抑制受体表达，一类T细胞表面表达的蛋白质直接限制 CD4+T细胞对微生物病原体的保护性免疫反应的能力。我们进一步 表明在疟疾期间阻断共抑制受体的活性可以恢复CD4+T细胞的功能， 促进强烈的抗体反应，加速寄生虫的控制和清除受感染的宿主。 最近，我们发现我们也可以通过以下方式恢复疟原虫特异性的CD4+T细胞的功能 激活T细胞刺激受体中的OX40。我们的新数据显示，在治疗方面 在实验性疟原虫感染的第二周刺激OX40受体可克服共同感染 抑制网络，显著提高CD4+T细胞活性和分泌抗体反应，并限制 疟疾寄生虫复制。重要的是，我们还在感染恶性疟原虫的儿童中发现了相似之处， 确立我们的发现的相关性和意义，并加强 目前的建议。在这个项目中，我们应用新的细胞、遗传和寄生虫学试剂来研究 OX40受体调节寄生虫特异性CD4+T细胞和B细胞之间的通讯 产生抗体反应。我们的科学问题和实验方法促进了我们长期的 学期目标是确定新的基于免疫的方法，以治疗性地刺激宿主对 疟疾。我们的目标是通过三个具体目标来实现的，这三个目标将决定：1) 独特调节CD4+T细胞上OX40受体功能表达的疟原虫感染；2) CD4+T细胞和B细胞之间的有效沟通是否需要OX40受体 产生强大的抗体反应；以及3)OX40配体的B细胞表达是否受 寄生虫的副产物，是产生有效的分泌抗体反应所必需的。我们建议的研究 新的试剂提供了易于处理的系统和可持续扩展的详细框架 该项目将建立更多新的范例，以增强CD4+T细胞介导的免疫对抗 疟原虫。我们在研究过程中获得的洞察力将帮助我们识别和开发新的免疫- 基于限制疟原虫疾病负担的战略。

PROJECT SUMMARY Plasmodium infections and the disease malaria remain global health emergencies. Malaria affected more than 200 million people last year, killing nearly 600,000. Antibody responses that target the parasite are essential for controlling parasite replication and limiting the severity of malaria. Potent antibody responses and optimally stimulated B cells require `help' from CD4+ T cells. Our published work has shown that CD4+ T cell function is markedly impaired following Plasmodium infection. We linked the reduced function of CD4+ T cells to the induction of co-inhibitory receptor expression, a class of T cell surface expressed proteins that directly limit the ability of CD4+ T cells to orchestrate protective immune responses against microbial pathogens. We further showed that blocking the activity of co-inhibitory receptors during malaria restored CD4+ T cell function, promoted strong antibody responses and accelerated parasite control and clearance from the infected host. Recently, we identified that we can also restore the function of Plasmodium-specific CD4+ T cells by activating OX40, a member of a class of T cell stimulating receptors. Our new data show that therapeutically stimulating the OX40 receptor during the second week of experimental Plasmodium infection overcomes co- inhibitory networks, markedly improves CD4+ T cell activity and secreted antibody responses, and limits malaria parasite replication. Importantly, we also identified parallels in children infected with P. falciparum, establishing the relevance and significance of our discoveries and strengthening the scientific premise of the current proposal. In this project we apply new cellular, genetic and parasitological reagents to study how the OX40 receptor regulates communication between parasite specific CD4+ T cells and B cells and the generation of antibody responses. Our scientific questions and experimental approaches facilitate our long- term goal to identify new immune-based approaches to therapeutically stimulate host resistance against malaria. Our goal is addressed by three specific aims that will determine: 1) the distinct characteristics of Plasmodium infection that uniquely regulate the functional expression of OX40 receptors on CD4+ T cells; 2) whether the OX40 receptor is required for effective communication between CD4+ T cells and B cells to generate potent antibody responses; and 3) whether B cell expression of the OX40 ligand is regulated by parasite byproducts and necessary for generating potent secreted antibody responses. Our proposed studies and new reagents provide tractable systems and a detailed framework for sustainable extensions of this project that will establish additional new paradigms for enhancing CD4+ T cell-mediated immunity against Plasmodium. Insight gained during the course of our studies will help us identify and develop new immune- based strategies to limit Plasmodium disease burden.