title: 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-2K(b) 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.
authors: Johns Hopkins Malaria Research Institute and Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America. icockbur@jhsph.edu
authors: Ian A
authors: IA
authors: Cockburn
authors: Sze-Wah
authors: SW
authors: Tse
authors: Andrea J
authors: AJ
authors: Radtke
authors: Prakash
authors: P
authors: Srinivasan
authors: Yun-Chi
authors: YC
authors: Chen
authors: Photini
authors: P
authors: Sinnis
authors: Fidel
authors: F
authors: Zavala
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005260:Female; D022781:Hepatocytes / Q000276:immunology*; D008288:Malaria / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D010962:Plasmodium berghei / Q000235:genetics / Q000276:immunology*; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D000953:Antigens, Protozoan; D000939:Epitopes; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan