IL-15 complex-stimulated NK cells protect mice from cerebral malaria

Abstract

Abstract Cerebral malaria (CM) is one of the most lethal complications of Plasmodium falciparum infection, responsible for a large fraction of the nearly one million malaria-related deaths annually. Infection of susceptible mouse strains such as C57BL/6 with Plasmodium berghei ANKA (PbA) induces a fatal neurological syndrome from 6–10 days post-infection (dpi) resulting from CD8 T cell-mediated damage to the CNS. We found that treatment of C57BL/6 mice with interleukin (IL)-15 complexes (IL-15C; IL-15 bound to an IL-15Rα-Fc fusion protein) prevented the development of PbA-induced CM. Rescue from CM was not associated with reduced parasitemia at 5 dpi. Instead, IL-15C treatment resulted in reduced CD8 T cell activation in the brain at 6 dpi and reduced blood brain barrier breakdown. In addition, adoptive transfer of IL-15C-stimulated natural killer (NK) cells (but not CD8+ T cells) was sufficient to prevent CM. IL-15C and similar complexes formed with IL-2 (IL-2C; IL-2 bound to the anti-IL-2 S4B6 antibody) both cause robust expansion and activation of NK cells but, unexpectedly, NK cells from mice treated with IL-2C failed to protect against CM. Comparative RNAseq analysis of IL-15C and IL-2C-treated NK cells identified novel gene expression patterns, demonstrating previously unappreciated differences between these cytokine complex signaling cascades in NK cells; the functional significance of these differences is being assessed. These data indicate that NK cells – which are typically involved in promoting inflammatory responses – can restrain damaging immune responses, and that differences between the activation of NK cells by IL-2C and IL-15C regulates their capacity to control the inflammatory response to blood stage malaria infection.