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Naive Precursor Frequencies and MHC Binding Rather Than the Degree of Epitope Diversity Shape CD8⁺ T Cell Immunodominance¹

Maya F. Kotturi^*, Iain Scott, Tom Wolfe, Bjoern Peters^*, John Sidney^*, Hilde Cheroutre, Matthias G. von Herrath, Michael J. Buchmeier, Howard Grey^* and Alessandro Sette^2,*

^* Division of Vaccine Discovery and Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and Department of Molecular Biology and Biochemistry and Department of Community and Environmental Medicine, University of California, Irvine, CA 92697

The primary CD8⁺ T cell response of C57BL/6J mice against the 28 known epitopes of lymphocytic choriomeningitis virus (LCMV) is associated with a clear immunodominance hierarchy whose mechanism has yet to be defined. To evaluate the role of epitope competition in immunodominance, we manipulated the number of CD8⁺ T cell epitopes that could be recognized during LCMV infection. Decreasing epitope numbers, using a viral variant lacking dominant epitopes or C57BL/6J mice lacking H-2K^b, resulted in minor response increases for the remaining epitopes and no new epitopes being recognized. Increasing epitope numbers by using F₁ hybrid mice, delivery by recombinant vaccinia virus, or epitope delivery as a pool in IFA maintained the overall response pattern; however, changes in the hierarchy did become apparent. MHC binding affinity of these epitopes was measured and was found to not strictly predict the hierarchy since in several cases similarly high binding affinities were associated with differences in immunodominance. In these instances the naive CD8⁺ T cell precursor frequency, directly measured by tetramer staining, correlated with the response hierarchy seen after LCMV infection. Finally, we investigated an escape mutant of the dominant GP33–41 epitope that elicited a weak response following LCMV variant virus infection. Strikingly, dominance loss likely reflects a substantial reduction in frequencies of naive precursors specific for this epitope. Thus, our results indicate that an intrinsic property of the epitope (MHC binding affinity) and an intrinsic property of the host (naive precursor frequency) jointly dictate the immunodominance hierarchy of CD8⁺ T cell responses.

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 Grant NIH-AI-50840 (to M.J.B.) and contract N01-AI-40023 (to A.S.).

² Address correspondence and reprint requests to Dr. Alessandro Sette, Division of Vaccine Discovery, 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: LCMV, lymphocytic choriomeningitis virus; NP, nucleoprotein; VACV, vaccinia virus; ICCS, intracellular cytokine staining; BFA, brefeldin A.