Dendritic cells and hepatocytes use distinct pathways to process protective antigen from Plasmodium in vivo

Ian A. Cockburn, Sze Wah Tse, Andrea J. Radtke, Prakash Srinivasan, Yun Chi Chen, Photini Sinnis, Fidel P Zavala

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere1001318
JournalPLoS Pathogens
Volume7
Issue number3
DOIs
StatePublished - Mar 2011

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Plasmodium
Dendritic Cells
Hepatocytes
Antigens
Epitopes
T-Lymphocytes
Parasites
Cytosol
Proteins
Cross-Priming
Sporozoites
Amino Acid Motifs
Endosomes
Mutant Proteins
Cytochromes c
Culicidae
Transgenic Mice
Malaria
Injections
Liver

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Dendritic cells and hepatocytes use distinct pathways to process protective antigen from Plasmodium in vivo. / Cockburn, Ian A.; Tse, Sze Wah; Radtke, Andrea J.; Srinivasan, Prakash; Chen, Yun Chi; Sinnis, Photini; Zavala, Fidel P.

In: PLoS Pathogens, Vol. 7, No. 3, e1001318, 03.2011.

Research output: Contribution to journalArticle

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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.",
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