Development and function of CD4+ memory T cells during malaria

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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.