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* Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
School of Biochemistry and Molecular Biology, Australian National University, Canberra, Australian Capital Territory, Australia; and
Institut de Biologie et Technologies de Saclay, Service d'Ingénierie Moléculaire des Protéines, Commissariat à l'Energie Atomique-Saclay, Gif sur Yvette, France
Understanding immunity to vaccinia virus (VACV) is important for the development of safer vaccines for smallpox- and poxvirus-vectored recombinant vaccines. VACV is also emerging as an outstanding model for studying CD8+ T cell immunodominance because of the large number of CD8+ T cell epitopes known for this virus in both mice and humans. In this study, we characterize the CD8+ T cell response in vaccinated BALB/c mice by a genome-wide mapping approach. Responses to each of 54 newly identified H-2d-restricted T cell epitopes could be detected after i.p. and dermal vaccination routes. Analysis of these new epitopes in the context of those already known for VACV in mice and humans revealed two important findings. First, CD8+ T cell epitopes are not randomly distributed across the VACV proteome, with some proteins being poorly or nonimmunogenic, while others are immunoprevalent, being frequently recognized across diverse MHC haplotypes. Second, some proteins constituted the major targets of the immune response by a specific haplotype as they recruited the majority of the specific CD8+ T cells but these proteins did not correspond to the immunoprevalent Ags. Thus, we found a dissociation between immunoprevalence and immunodominance, implying that different sets of rules govern these two phenomena. Together, these findings have clear implications for the design of CD8+ T cell subunit vaccines and in particular raise the exciting prospect of being able to choose subunits without reference to MHC restriction.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the National Institutes of Health, through Contract HHSN266200400024C, and R01 Grants AI-56268 (to A.S.) and AI067401 (to D.C.T.). D.C.T. is supported by Australian National Health and Medical Research Council Career Development Award 418108.
2 Address correspondence and reprint requests to Dr. Alessandro Sette, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037. E-mail address: alex{at}liai.org
3 Abbreviations used in this paper: VACV, vaccinia virus; ORF, open reading frame; MOI, multiplicity of infection; WR, Western Reserve; SFC, spot-forming cell; ICCS, intracellular cytokine staining.
4 The online version of this article contains supplemental material.
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  V. S. Meyer, W. Kastenmuller, G. Gasteiger, M. Franz-Wachtel, T. Lamkemeyer, H.-G. Rammensee, S. Stevanovic, D. Sigurdardottir, and I. Drexler Long-Term Immunity against Actual Poxviral HLA Ligands as Identified by Differential Stable Isotope Labeling J. Immunol., November 1, 2008; 181(9): 6371 - 6383. [Abstract] [Full Text] [PDF]
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