Malaria is a devastating global health problem that has been exacerbated by the emergence of drug- resistant parasites. Thus, new approaches to combat malaria such as immune interventions are needed. The most severe complication of this disease is cerebral malaria (CM), which causes around a million deaths annually, mainly in young children. Infection of susceptible mouse strains such as C57BL/6 with Plasmodium berghei ANKA (P.b. ANKA) recapitulates many aspects of the human disease and has been studied to identify which components of the immune system are responsible for the development of CM. A number of studies have demonstrated that excessive immune activation - including robust proinflammatory cytokine production and T cell activation - is the driver of lethal CM. Thus, identifying ways to prevent or intervene in the immune-mediated pathology would limit the severity of this disease and potentially other immunopathologic diseases. Preliminary data presented in this application identifies that treatment with of C57BL/6 mice with IL-15 complexes (IL-15C; IL-15 bound to an IL-15Ra-Fc fusion protein) completely blocked P.b. ANKA-induced fatal brain inflammatory disease, while treatment with IL-2 complexes (IL-2C; IL-2 bound to the anti-IL-2 S4B6 antibody) did not. Il-15C and IL-2C signal through the same receptor components and induce expansion of both CD8 T cells and NK cells. Intriguingly, we observed that IL-15C-treated NK cells were essential for protection against CM in this model. Furthermore, adoptive transfer of NK cells treated with IL-15C (but not IL-2C) was sufficient to prevent CM induction, suggesting that this NK cell population dominantly protects against this fatal disease. These data identify a novel distinction between lymphocyte activation by IL-15 and IL-2. Thus, we hypothesize that IL-15C treatment generates a protective NK cell population distinct from IL-2C-treated NK cells. In Aim 1, phenotypic and functional analyses will be performed following IL-15C or IL-2C treatment, with or without P.b. ANKA infection, to delineate the specific differences generated by cytokine complex treatment and determine the mechanism(s) required by IL-15C-treated NK cells to prevent the development of CM. Specifically, we propose that IL-15C-stimulated NK cells inhibit the pathologic T cell response, resulting in protection from CM. Hence, Aim 2 will assess the immunoregulatory properties of IL-15C-treated NK cells on T cells with a specific emphasis on examining the cytolytic and inhibitory effect NK cells can exert on T cells. Collectively, the proposed investigations will characterize the previously unappreciated distinction between NK cell activation by IL-15C and IL-2C and greatly expand our knowledge of the effects of cytokine complex therapy in the presence and absence of an infection. In addition, these studies will yield novel insights into the basis for the IL-15C-treated NK cell-mediated control of CM. A mechanistic understanding of CM pathogenesis and the process of cytokine complex perturbation will provide an important foundation for the identification of new therapeutic targets and aid in the development of innovative strategies for effectively treating severe malaria and potentially other immunopathologic diseases.