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Journal of Virology, May 2002, p. 4251-4259, Vol. 76, No. 9
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.9.4251-4259.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Immunodominance in Virus-Induced CD8+ T-Cell Responses Is Dramatically Modified by DNA Immunization and Is Regulated by Gamma Interferon{dagger}

Fernando Rodriguez,1,2 Stephanie Harkins,1 Mark K. Slifka,1,3 and J. Lindsay Whitton1*

Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037,1 Unidad de Investigacion, Hospital Universitario 12 de Octubre, Madrid, Spain,2 Oregon Health Sciences University Vaccine and Gene Therapy Institute, Beaverton, Oregon 970063

Received 2 November 2001/ Accepted 28 January 2002

The phenomenon whereby the host immune system responds to only a few of the many possible epitopes in a foreign protein is termed immunodominance. Immunodominance occurs not only during microbial infection but also following vaccination, and clarification of the underlying mechanism may permit the rational design of vaccines which can circumvent immunodominance, thereby inducing responses to all epitopes, dominant and subdominant. Here, we show that immunodominance affects DNA vaccines and that the effects can be avoided by the simple expedient of epitope separation. DNA vaccines encoding isolated dominant and subdominant epitopes induce equivalent responses, confirming a previous demonstration that coexpression of dominant and subdominant epitopes on the same antigen-presenting cell (APC) is central to immunodominance. We conclude that multiepitope DNA vaccines should comprise a cocktail of plasmids, each with its own epitope, to allow maximal epitope dispersal among APCs. In addition, we demonstrate that subdominant responses are actively suppressed by dominant CD8+ T-cell responses and that gamma interferon (IFN-{gamma}) is required for this suppression. Furthermore, priming of CD8+ T cells to a single dominant epitope results in strong suppression of responses to other normally dominant epitopes in immunocompetent mice, in effect rendering these epitopes subdominant; however, responses to these epitopes are increased 6- to 20-fold in mice lacking IFN-{gamma}. We suggest that, in agreement with our previous observations, IFN-{gamma} secretion by CD8+ T cells is highly localized, and we propose that its immunosuppressive effect is focused on the APC with which the dominant CD8+ T cell is in contact.

* Corresponding author. Mailing address: Department of Neuropharmacology, CVN-9, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-7090. Fax: (858) 784-7380. E-mail: lwhitton{at}scripps.edu.

{dagger} Manuscript 12304-NP from The Scripps Research Institute.

Journal of Virology, May 2002, p. 4251-4259, Vol. 76, No. 9
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.9.4251-4259.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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Copyright © 2002 by the American Society for Microbiology. All rights reserved.