IL-15 complex modulates the Plasmodium-specific CD4 T cell response in mice

Abstract

Abstract Malaria, which results from infection with Plasmodium parasites, remains a major public health problem with over 200 million cases and nearly 500,000 deaths annually. CD4 T helper cells, especially T follicular helper (Tfh) cells, provide help to B cells to induce effective antibody responses. Although long-lived, sterilizing immunity does not develop in humans following repeated exposure to Plasmodium parasites, protection against symptomatic disease correlates with the acquisition of humoral immunity. The study of parasite-specific CD4 T cell responses has been hampered by the lack of defined parasite-derived T cell epitopes. Utilizing newly identified CD4 T cell epitopes, we generated novel peptide:MHC class II tetramers to track Plasmodium-specific CD4 T cells in mice following infection with multiple rodent Plasmodium strains, including Plasmodium berghei ANKA (PbA), P. berghei NK65 and P. yoelii. Infection of susceptible mice with PbA results in a fatal severe malaria disease. We previously showed that treatment of mice with IL-15 complex (IL-15C; IL-15 bound to an IL-15Rα-Fc fusion protein) induces IL-10 expression in NK cells and protects mice from PbA-induced death. IL-15C treatment results in reduced Ag-specific CD4 T cells on day 6 post-infection but an increased ratio of regulatory T cells to Tfh cells. These data suggest that IL-15C treatment, via its induction of IL-10 from NK cells, modulates the Ag-specific CD4 T cell response, with potential downstream effects on the germinal center reaction and antibody responses. We propose that analysis of the Plasmodium-specific CD4 T cell response will inform the design of therapeutics and vaccine strategies for Plasmodium infection.