Heat-Aggregated Noninfectious Influenza Virus Induces a More Balanced CD8+-T-Lymphocyte Immunodominance Hierarchy Than Infectious Virus

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Abstract
CD8+-T-cell (TCD8+) responses to infectious viruses are characterized by an immunodominance hierarchy in which the majority of TCD8+ respond to one or a few immunodominant determinants, with a minority of TCD8+ responding to a number of subdominant determinants. It is now well established that exogenous antigens are capable of inducing TCD8+ 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 TCD8+ responses to influenza virus preparations rendered inert by incubation for 10 min at 100°C, as first reported by Speidel et al. (Eur. J. Immunol. 27:2391-2399, 1997). Extending these findings, we show that the primary TCD8+ 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 TCD8+ induced by infectious virus. Importantly, the immunodominance hierarchy elicited was leveled, and we were unable to detect TCD8+ 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 TCD8+ responses.