Dendritic Cells and Hepatocytes Use Distinct Pathways to Process Protective Antigen from Plasmodium in vivo

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.

CD8+T Cells Specific for a Malaria Cytoplasmic Antigen Form Clusters around Infected Hepatocytes and Are Protective at the Liver Stage of Infection

“…3C). These results strongly suggest that hepatocytes infected with PbA-hsOVA sporozoites process and present the OVA epitope via the classical MHC class I pathway, which is consistent with the findings of a previous study using P. berghei expressing a mutant CS protein containing an OVA epitope (39).…”

Systemic Toll-Like Receptor Ligation and Selective Killing of Dendritic Cell Subsets Fail To Dissect Priming Pathways for Anti-Vaccinia Virus CD8+T Cells

“…These two methods have been very well published in studies of CD8 ϩ T cell-priming pathways (10,12,13,(15)(16)(17)(18)(19)(20). While the CpG method has been applied in separate studies to VACV WR and MVA, there has not been a direct comparison of cross-and direct priming with these strains.…”

Dendritic cells treated with crude Plasmodium berghei extracts acquire immune‐modulatory properties and suppress the development of autoimmune neuroinflammation

“…During the Plasmodium infection, the parasite develops tropism towards DCs, which phagocytose the infected RBCs. 35,36 Inside DCs, the parasite produces hemozoin, a product of haemoglobin degradation, ultimately leading to impaired DC maturation. 12 In vitro hemozoin-treated DCs acquire immunosuppressive abilities such as reduced expression of co-stimulatory molecules CD80 and CD86, secretion of IL-10 and induction of Treg cells.…”