Abstract
Malaria-protective CD8+ T cells specific for the circumsporozoite (CS) protein are primed by dendritic cells (DCs) after sporozoite injection by infected mosquitoes. The primed cells then eliminate parasite liver stages after recognizing the CS epitopes presented by hepatocytes. To define the in vivo processing of CS by DCs and hepatocytes, we generated parasites carrying a mutant CS protein containing the H-2Kb epitope SIINFEKL, and evaluated the T cell response using transgenic and mutant mice. We determined that in both DCs and hepatocytes CS epitopes must reach the cytosol and use the TAP transporters to access the ER. Furthermore, we used endosomal mutant (3d) and cytochrome c treated mice to address the role of cross-presentation in the priming and effector phases of the T cell response. We determined that in DCs, CS is cross-presented via endosomes while, conversely, in hepatocytes protein must be secreted directly into the cytosol. This suggests that the main targets of protective CD8+ T cells are parasite proteins exported to the hepatocyte cytosol. Surprisingly, however, secretion of the CS protein into hepatocytes was not dependent upon parasite-export (Pexel/VTS) motifs in this protein. Together, these results indicate that the presentation of epitopes to CD8+ T cells follows distinct pathways in DCs when the immune response is induced and in hepatocytes during the effector phase.
Highlights
Immunization with irradiated Plasmodium sporozoites to induce sterile protection against live parasite challenge is a powerful model for malaria vaccination [1]
Since immunization with irradiated sporozoites represents the gold standard for malaria vaccination it is important to know which sporozoite antigens are presented by dendritic cells (DCs)
In this study we aimed to identify key cellular and molecular features of the antigen processing pathways employed by DCs and hepatocytes
Summary
Immunization with irradiated Plasmodium sporozoites to induce sterile protection against live parasite challenge is a powerful model for malaria vaccination [1]. We have found that after sporozoite inoculation into the dermis by infected mosquitoes, antigen is presented by DCs in the skin-draining lymph node to initiate the CD8+ T cell response [4]. CD8+ T cell mediated immunity requires antigen presentation by two different cell types – DCs and hepatocytes. Since immunization with irradiated sporozoites represents the gold standard for malaria vaccination it is important to know which sporozoite antigens are presented by DCs. Perhaps more vital still, is to understand which molecules are presented by hepatocytes, as only those molecules presented to effector cells can be the targets of protective immunity
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