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Journal of Virology, April 2003, p. 4679-4684, Vol. 77, No. 8
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.8.4679-4684.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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

Yunjung Cho, Sameh Basta, Weisan Chen, Jack R. Bennink, and Jonathan W. Yewdell^*

Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892

Received 10 October 2002/ Accepted 23 January 2003

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°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.

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* Corresponding author. Mailing address: Rm. 211, Bldg. 4, 4 Center Dr., MSC 0440, National Institutes of Health, Bethesda, MD 20892-0440. Phone: (301) 402-4602. Fax: (301) 402-7362. E-mail: jyewdell{at}nih.gov.

Present address: Department of Clinical Pathology, Korea University Medical Center Anam Hospital, 126-1 Seoul, Korea 136-705.

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Journal of Virology, April 2003, p. 4679-4684, Vol. 77, No. 8
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.8.4679-4684.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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