Development and function of CD4+ memory T cells during malaria

项目总结 疟原虫感染和疟疾仍然是全球卫生紧急情况。疟原虫寄生虫 在体内复制并导致宿主红细胞的破坏，这会引发炎症并导致 疟疾的症状。感染后产生的寄生虫特异性抗体反应是至关重要的 用于控制寄生虫负担和限制疾病严重程度。CD4+辅助性T细胞对协调 这些保护性抗体反应。然而，绝育的抗疟原虫免疫很少发展，甚至 在反复感染之后。我们推测这是由于疟原虫特异性效应器和记忆力不足所致 CD4+T细胞的发育和功能。开发新的基于免疫系统的最关键的挑战之一 针对疟原虫的治疗或疫苗正在了解长寿疟原虫- 在感染后，特定记忆的CD4+T细胞会发育、发挥功能并持续存在。 在这个项目的继续过程中，我们应用了强大的新细胞和分子遗传学方法 实现对疟原虫特异性记忆CD4+T细胞的直接、高分辨率分析。这些新方法 促进我们的长期目标，以了解管理发展和功能的机制 疟原虫特异性记忆中的CD4+T细胞反应。我们的目标通过三个具体目标来实现，这三个目标具有 进化到测试：1)血球蛋白，一种寄生虫衍生的血红蛋白降解产物，如何影响诱导 和维持疟原虫特异性记忆的CD4+T细胞群；2)如何限制宿主细胞 新陈代谢、形状记忆、CD4+T细胞的形成和功能；以及3)特定的表观遗传调节因子如何调控 CD4+记忆T细胞的分化和功能。我们的创新概念和技术进步以及 机械化的方法使我们能够建立更多的新范式来理解和加强 CD4+T细胞依赖的抗疟原虫免疫。了解以下免疫记忆的形成 疟原虫感染将使我们能够识别和开发新的基于免疫的策略来限制疟原虫 病机与疾病负担。

PROJECT SUMMARY Plasmodium infections and the disease malaria remain global health emergencies. Plasmodium parasites replicate within and cause the destruction of host red blood cells, which triggers inflammation and causes the symptoms of malarial disease. Parasite-specific antibody responses that develop following infection are critical for controlling parasite burden and limiting disease severity. CD4+ helper T cells are essential for coordinating these protective antibody responses. However, sterilizing anti-Plasmodium immunity rarely develops, even following repeated infection. We hypothesize this is due to deficient Plasmodium-specific effector and memory CD4+ T cell development and function. One of the most critical challenges to developing new immune-based therapies or vaccines against Plasmodium is understanding the mechanisms by which long-lived Plasmodium- specific memory CD4+ T cells develop, function and persist following infection. In the continuation of this project, we apply powerful new cellular and molecular genetic approaches that enable direct, high-resolution analyses of Plasmodium-specific memory CD4+ T cells. These new approaches facilitate our long-term goal to understand the mechanisms governing the development and function of Plasmodium-specific memory CD4+ T cell responses. Our goal is addressed by three specific aims that have evolved to test: 1) how hemozoin, a parasite-derived product of hemoglobin degradation, influences the induction and maintenance of Plasmodium-specific memory CD4+ T cell populations; 2) how constraints on host cellular metabolism shape memory CD4+ T cell formation and function; and 3) how specific epigenetic regulators govern the differentiation and function of CD4+ memory T cells. Our innovative conceptual and technical advances and mechanistic approaches enable us to establish additional new paradigms for understanding and enhancing CD4+ T cell-dependent anti-Plasmodium immunity. Understanding immune memory formation following Plasmodium infection will enable us to identify and develop new immune-based strategies to limit Plasmodium pathogenesis and disease burden.