Regulation of Plasmodium-specific CD4+ T cells

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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 immune failures are mechanistically linked to aberrant or inefficient Plasmodium-specific effector 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 Plasmodium-specific CD4+ T cells develop, function and regulate humoral immunity 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 CD4+ T cells. These new approaches facilitate our long-term goal to understand the mechanisms governing the development and function of Plasmodium- specific CD4+ T cell responses. Our goal is addressed by two specific aims that have evolved to test: 1) how parasite-derived molecules influence cell antigen presenting functions and priming of Plasmodium-specific CD4+ T populations; and 2) how host physiological perturbations and constraints on cellular metabolism regulate CD4+ T cell development and function. 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 cellular and molecular events governing CD4 T+ T cell responses during malaria will enable us to identify and develop new immune-based strategies to limit Plasmodium pathogenesis and disease burden.