Development and function of CD4+ memory T cells during malaria

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，从而引发炎症并导致 疟疾的症状。感染后产生的寄生虫特异性抗体反应至关重要 用于控制寄生虫负担和限制疾病严重程度。CD4+辅助性T细胞是协调免疫系统的关键。 这些保护性抗体反应。然而，杀菌抗疟原虫免疫很少发展，即使 反复感染后。我们推测这是由于缺乏疟原虫特异性效应子和记忆 CD4 + T细胞形成。开发新的基于免疫的疗法或 针对疟原虫的疫苗正在了解长寿命疟原虫特异性记忆CD4 + T细胞在感染后发育、发挥功能并持续存在。在这个项目中，我们开发了强大的新 细胞、遗传和生物化学方法，能够直接、高分辨率地分析真正的 疟原虫特异性记忆性CD4 + T细胞。这些新方法有助于我们实现长期目标， 疟原虫特异性记忆性CD4 + T细胞应答的数量和质量。我们的目标是通过 三个具体的检测目标：1）疟原虫特异性效应子的表型、功能和数量稳定性 和记忆CD 4 + T细胞群及其对保护性体液免疫的影响; 2）寄生虫和 宿主特异性因子调节长寿命记忆性CD4 + T细胞应答的形成;和3）效应子 记忆性CD4 + T细胞用于协调长寿抗疟原虫免疫的机制和途径。 我们的创新方法使我们能够建立更多的新范式， CD4 + T细胞依赖性抗疟原虫免疫。了解免疫记忆的形成 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 发病机制和疾病负担。

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 formation. One of the most critical challenges to developing new immune-based therapies or vaccines against Plasmodium is understanding how or whether long-lived Plasmodium-specific memory CD4+ T cells develop, function and persist following infection. In this project we have developed powerful new cellular, genetic and biochemical approaches that enable direct, high-resolution analyses of bona fide Plasmodium-specific memory CD4+ T cells. These new approaches facilitate our long-term goal to understand the quantity and quality of Plasmodium-specific memory CD4+ T cell responses. Our goal is addressed by three specific aims that test: 1) the phenotype, function and numerical stability of Plasmodium-specific effector and memory CD4+ T cell populations and their impact on protective humoral immunity; 2) how parasite- and host-specific factors regulate the formation of long-lived memory CD4+ T cell responses; and 3) the effector mechanisms and pathways that memory CD4+ T cells use to orchestrate long-lived anti-Plasmodium immunity. Our innovative 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.