Immunization with Radiation-Attenuated Plasmodium berghei Sporozoites Induces Liver cCD8α+DC that Activate CD8+T Cells against Liver-Stage Malaria

Immunization with radiation (gamma)-attenuated Plasmodia sporozoites (gamma-spz) confers sterile and long-lasting immunity against malaria liver-stage infection. In the P. berghei gamma-spz model, protection is linked to liver CD8(+) T cells that express an effector/memory (T-EM) phenotype, (CD(44hi)CD45RB(lo)CD62L(lo)), and produce IFN-gamma. However, neither the antigen presenting cells (APC) that activate these CD8(+) T-EM cells nor the site of their induction have been fully investigated. Because conventional (c) CD8 alpha(+) DC (a subset of CD11c(+) DC) are considered the major inducers of CD8(+) T cells, in this study we focused primarily on cCD8 alpha(+) DC from livers of mice immunized with Pb gamma-spz and asked whether the cCD8 alpha(+) DC might be involved in the activation of CD8(+) T-EM cells. We demonstrate that multiple exposures of mice to Pb gamma-spz lead to a progressive and nearly concurrent accumulation in the liver but not the spleen of both the CD11c(+)NK1.1(-) DC and CD8(+) T-EM cells. Upon adoptive transfer, liver CD11c(+)NK1.1(-) DC from Pb gamma-spz-immunized mice induced protective immunity against sporozoite challenge. Moreover, in an in vitro system, liver cCD8 alpha(+) DC induced naive CD8(+) T cells to express the CD8(+) T-EM phenotype and to secrete IFN-gamma. The in vitro induction of functional CD8(+) T-EM cells by cCD8 alpha(+) DC was inhibited by anti-MHC class I and anti-IL-12 mAbs. These data suggest that liver cCD8 alpha(+) DC present liver-stage antigens to activate CD8(+) T-EM cells, the pre-eminent effectors against pre-erythrocytic malaria. These results provide important implications towards a design of anti-malaria vaccines.