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* Division of Vaccine Discovery and
Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and
Department of Microbiology, Molecular and Genetic Bioinformatics Facility, University of Alabama, Birmingham, AL 35294
Recent studies have defined vaccinia virus (VACV)-specific CD8+ T cell epitopes in mice and humans. However, little is known about the epitope specificities of CD4+ T cell responses. In this study, we identified 14 I-Ab-restricted VACV-specific CD4+ T cell epitopes by screening a large set of 2146 different 15-mer peptides in C57BL/6 mice. These epitopes account for 
20% of the total anti-VACV CD4+ T cell response and are derived from 13 different viral proteins. Surprisingly, none of the CD4+ T cell epitopes identified was derived from VACV virulence factors. Although early Ags were recognized, late Ags predominated as CD4+ T cell targets. These results are in contrast to what was previously found in CD8+ T cells responses, where early Ags, including virulence factors, were prominently recognized. Taken together, these results highlight fundamental differences in immunodominance of CD4+ and CD8+ T cell responses to a complex pathogen.
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 study was funded by the National Institute of Health Contract HHSN266200400024C and Contract HHSN266200400036C (to E.J.L.) and R01 Grant R01-AI-56268. Kirin Publication No. 837.
2 Address correspondence and reprint requests to Dr. Alessandro Sette, 9420 Athena Circle, La Jolla, CA 92037. E-mail address: alex{at}liai.org
3 Abbreviations used in this paper: VACV, vaccinia virus; WR, Western Reserve; SFC, spot-forming cells; LPS-Blasts, LPS-stimulated B lymphoblasts; DC, dendritic cell; ICCS, intracellular cytokine staining; SI, stimulation index; HCMV, human CMV.
4 The online version of this article contains supplemental material.
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