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J. Biol. Chem., Vol. 278, Issue 46, 45135-45144, November 14, 2003

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Genome-wide Characterization of a Viral Cytotoxic T Lymphocyte Epitope Repertoire^*

Weimin Zhong, Pedro A. Reche, Char-Chang Lai, Bruce Reinhold, and Ellis L. Reinherz

From the Laboratory of Immunobiology and Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115

A genome-wide search using major histocompatibility complex (MHC) class I binding and proteosome cleavage site algorithms identified 101 influenza A PR8 virus-derived peptides as potential epitopes for CD8⁺ T cell recognition in the H-2^b mouse. Cytokine-based flow cytometry, ELISPOT, and cytotoxic T lymphocyte assays reveal that 16 are recognized by CD8⁺ T cells recovered directly ex vivo from infected animals, accounting for greater than 70% of CD8⁺ T cells recruited to lung after primary infection. Only six of the 22 highest affinity MHC class I binding peptides comprise cytotoxic T lymphocyte epitopes. The remaining non-immunogenic peptides have equivalent MHC affinity and MHC-peptide complex half-lives, eliciting T cell responses when given in adjuvant and with T cell receptor-ligand avidity comparable with their immunogenic counterparts. As revealed by a novel high sensitivity nanospray tandem mass spectrometry methodology, failure to process those predicted epitopes may contribute significantly to the absent response. These results have important implications for rationale design of CD8⁺ T cell vaccines.

Received for publication, July 10, 2003 , and in revised form, August 1, 2003.

^* This work was supported by National Institutes of Health Grant AI50900 and an award from the Molecular Immunology Foundation. 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.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Material and Supplemental Figs. S1–S11 and Tables S1 and S2.

To whom correspondence should be addressed: Dana-Farber Cancer Inst., 44 Binney St., Boston, MA 02115. Tel.: 617-632-3412; Fax: 617-632-3351; E-mail: ellis_reinherz{at}dfci.harvard.edu.

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