title: Heat-aggregated noninfectious influenza virus induces a more balanced CD8(+)-T-lymphocyte immunodominance hierarchy than infectious virus.
abstract: CD8(+)-T-cell (T(CD8+)) responses to infectious viruses are characterized by an immunodominance hierarchy in which the majority of T(CD8+) respond to one or a few immunodominant determinants, with a minority of T(CD8+) responding to a number of subdominant determinants. It is now well established that exogenous antigens are capable of inducing T(CD8+) to such immunodominant determinants, but the diversity of the response and the nature of the immunodominance hierarchy have not been examined. We addressed this issue by characterizing T(CD8+) responses to influenza virus preparations rendered inert by incubation for 10 min at 100 degrees C, as first reported by Speidel et al. (Eur. J. Immunol. 27:2391-2399, 1997). Extending these findings, we show that the primary T(CD8+) response to boiled virus can be sufficiently robust to be detected ex vivo by intracellular cytokine staining and that the response encompasses many of the peptides recognized by T(CD8+) induced by infectious virus. Importantly, the immunodominance hierarchy elicited was leveled, and we were unable to detect T(CD8+) that were specific for boiled virus. We used peritoneal exudate cells as antigen-presenting cells in vitro, and a number of observations indicated that boiled virus is processed via a phagocytic route that is likely to be endosomal in nature. These findings suggest that the repertoires of immunogenic peptides generated by endosomes and cytosolic processes overlap to a surprising degree. Furthermore, they demonstrate that the form of antigen administered can influence immunodominance hierarchies and that exogenous-antigen vaccines can induce broad and balanced T(CD8+) responses.
authors.affiliation: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Yunjung
authors.initials: Y
authors.lastname: Cho
authors.forename: Sameh
authors.initials: S
authors.lastname: Basta
authors.forename: Weisan
authors.initials: W
authors.lastname: Chen
authors.forename: Jack R
authors.initials: JR
authors.lastname: Bennink
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Yewdell
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D003713:Dendritic Cells; D006358:Hot Temperature; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D009980:Influenza A virus / Q000276:immunology* / Q000472:pathogenicity; D007252:Influenza Vaccines / Q000276:immunology; D007251:Influenza, Human / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D000956:Antigens, Viral; D016056:Immunodominant Epitopes; D007252:Influenza Vaccines