Immunodominance in virus-induced CD8+ T-cell responses is dramatically modified by DNA immunization and is regulated by gamma interferon

Fernando Rodriguez, Stephanie Harkins, Mark Slifka, J. Lindsay Whitton

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

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-γ) 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-γ. We suggest that, in agreement with our previous observations, IFN-γ 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.

Original languageEnglish (US)
Pages (from-to)4251-4259
Number of pages9
JournalJournal of Virology
Volume76
Issue number9
DOIs
StatePublished - 2002
Externally publishedYes

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interferon-gamma
epitopes
Interferon-gamma
Epitopes
Immunization
immunization
T-lymphocytes
Viruses
T-Lymphocytes
viruses
DNA
DNA Vaccines
recombinant vaccines
antigen-presenting cells
Antigen-Presenting Cells
interferons
Interferons
immunosuppressive agents
mice
rendering

ASJC Scopus subject areas

  • Immunology

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Immunodominance in virus-induced CD8+ T-cell responses is dramatically modified by DNA immunization and is regulated by gamma interferon. / Rodriguez, Fernando; Harkins, Stephanie; Slifka, Mark; Whitton, J. Lindsay.

In: Journal of Virology, Vol. 76, No. 9, 2002, p. 4251-4259.

Research output: Contribution to journalArticle

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