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

被引:77
作者
Cockburn, Ian A. [1 ,2 ]
Tse, Sze-Wah [1 ,2 ]
Radtke, Andrea J. [1 ,2 ]
Srinivasan, Prakash [1 ,2 ]
Chen, Yun-Chi [1 ,2 ]
Sinnis, Photini [3 ]
Zavala, Fidel [1 ,2 ]
机构
[1] Johns Hopkins Univ, Johns Hopkins Malaria Res Inst, Baltimore, MD 21218 USA
[2] Johns Hopkins Univ, Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA
[3] NYU, Sch Med, Dept Med Parasitol, New York, NY USA
关键词
CD8(+) T-CELLS; MALARIA LIVER-STAGES; CIRCUMSPOROZOITE PROTEIN; SPOROZOITE STAGE; TUMOR-IMMUNITY; LYMPH-NODES; HOST; ANTIBODIES; BERGHEI; PARASITE;
D O I
10.1371/journal.ppat.1001318
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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.
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页数:10
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