Abstract
Multiple exposures of humans and laboratory rodents to radiation-attenuated Plasmodium sporozoites (γ-spz) induce sterile and long-lasting protection that is thought to be directed mainly to liver-stage antigens (LS-Ags). Although protection involves B cells and CD4 T cells, MHC class I-dependent liver IFN-γ+ CD8 T cells are the key effectors against LS-Ags. Recently several LS-Ags have been shown to induce protection in murine models; nevertheless, the mechanism of processing and presentation of LS-Ag to CD8 T cells has not been investigated. We tested liver CD8 T cell responses induced by Plasmodium berghei (Pb) γ-spz in TAP-/- mice to inquire whether processing/presentation of the exogenous LS-Ags was TAP-dependent or -independent. Immunization with Pb γ-spz induced proliferation and IFN-γ production by liver CD8 T cells. Also, TAP-/- CD8 T cells eliminated hepatocytes infected with Pb sporozoites in vitro. Despite these effector activities, Pb γ-spz immunized TAP-/- mice were not protected against sporozoite infection, mainly because liver CD8 T effector cells failed to produce IFN-γ in response to infectious sporozoite challenge. Our results demonstrate that although TAP-independent vacuolar pathway operates efficiently during immunization with γ-spz, the TAP-associated phagosomal-to-cytosol antigen processing mechanism appears to be required for effective recall of effector CD8 T cells during infection. The implications of these findings will be discussed.
