Immunization with radiation-attenuated Plasmodium berghei sporozoites induces liver cCD8alpha+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, (CD44(hi)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)CD8alpha+ DC (a subset of CD11c+ DC) are considered the major inducers of CD8+ T cells, in this study we focused primarily on cCD8alpha+ DC from livers of mice immunized with Pb gamma-spz and asked whether the cCD8alpha+ 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 cCD8alpha(+) DC induced naïve 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 cCD8alpha+ DC was inhibited by anti-MHC class I and anti-IL-12 mAbs. These data suggest that liver cCD8alpha+ 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.
Department of Cellular Immunology, Division of Malaria Vaccine Development, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
Ousman
O
Jobe
Gina
G
Donofrio
Guangping
G
Sun
Dmitry
D
Liepinsh
Robert
R
Schwenk
Urszula
U
Krzych
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D008107:Liver Diseases / Q000276:immunology / Q000517:prevention & control*; D008213:Lymphocyte Activation; D008288:Malaria / Q000276:immunology / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000008:administration & dosage*; D051379:Mice; D010962:Plasmodium berghei / Q000254:growth & development*; D034101:Sporozoites / Q000276:immunology / Q000528:radiation effects
D017780:Malaria Vaccines