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

Immunization with radiation (γ)-attenuated Plasmodia sporozoites (γ-spz) confers sterile and long-lasting immunity against malaria liver-stage infection. In the P. berghei γ-spz model, protection is linked to liver CD8(+) T cells that express an effector/memory (T(EM)) phenotype, (CD44(hi)CD45RB(lo)CD62L(lo) ), and produce IFN-γ. 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)CD8α(+) DC (a subset of CD11c(+) DC) are considered the major inducers of CD8(+) T cells, in this study we focused primarily on cCD8α(+) DC from livers of mice immunized with Pb γ-spz and asked whether the cCD8α(+) DC might be involved in the activation of CD8(+) T(EM) cells. We demonstrate that multiple exposures of mice to Pb γ-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 γ-spz-immunized mice induced protective immunity against sporozoite challenge. Moreover, in an in vitro system, liver cCD8α(+) DC induced naïve CD8(+) T cells to express the CD8(+) T(EM) phenotype and to secrete IFN-γ. The in vitro induction of functional CD8(+) T(EM) cells by cCD8α(+) DC was inhibited by anti-MHC class I and anti-IL-12 mAbs. These data suggest that liver cCD8α(+) 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.