title: Cross-priming utilizes antigen not available to the direct presentation pathway.
abstract: CD8+ T cells play a crucial role in protective immunity to viruses and tumours. Antiviral CD8+ T cells are initially activated by professional antigen presenting cells (pAPCs) that are directly infected by viruses (direct-priming) or following uptake of exogenous antigen transferred from virus-infected or tumour cells (cross-priming). In order to efficiently target each of these antigen-processing pathways during vaccine design, it is necessary to delineate the properties of the natural substrates for either of these antigen-processing pathways. In this study, we utilized a novel T-cell receptor (TCR) transgenic mouse to examine the requirement for both antigen synthesis and synthesis of other cellular factors during direct or cross-priming. We found that direct presentation required ongoing synthesis of antigen, but that cross-priming favoured long-lived antigens and did not require ongoing antigen production. Even after prolonged blockade of protein synthesis in the donor cell, cross-priming was unaffected. In contrast, direct-presentation was almost undetectable in the absence of antigen neosynthesis and required ongoing protein synthesis. This suggests that the direct- and cross-priming pathways may utilize differing pools of antigen, an observation that has far-reaching implications for the rational design of vaccines aimed at the generation of protective CD8+ T cells.
authors.affiliation: Department of Microbiology and Immunology, Pennsylvania State University, Milton S. Hershey College of Medicine, Hershey, PA 17033-0850, USA.
authors.forename: Keri B
authors.initials: KB
authors.lastname: Donohue
authors.forename: Jean M
authors.initials: JM
authors.lastname: Grant
authors.forename: Eric F
authors.initials: EF
authors.lastname: Tewalt
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Palmer
authors.forename: Marc R
authors.initials: MR
authors.lastname: Theoret
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Norbury
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology*; D000941:Antigens / Q000096:biosynthesis / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D045142:Cross-Priming / Q000502:physiology*; D003513:Cycloheximide / Q000494:pharmacology; D018274:Electroporation; D005434:Flow Cytometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology / Q000517:prevention & control; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D014777:Virus Diseases / Q000276:immunology* / Q000517:prevention & control
chemical_list: D000941:Antigens; D011500:Protein Synthesis Inhibitors; D011948:Receptors, Antigen, T-Cell; D003513:Cycloheximide