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The Journal of Immunology, 2004, 173: 5021-5027.
Copyright © 2004 by The American Association of Immunologists

Reversal in the Immunodominance Hierarchy in Secondary CD8+ T Cell Responses to Influenza A Virus: Roles for Cross-Presentation and Lysis-Independent Immunodomination1

Weisan Chen*, Ken Pang*, Kelly-Anne Masterman*, Gina Kennedy*, Sameh Basta{dagger}, Nektaria Dimopoulos*, Felicita Hornung{dagger}, Mark Smyth{ddagger}, Jack R. Bennink{dagger} and Jonathan W. Yewdell2,{dagger}

* T Cell Laboratory, Ludwig Institute for Cancer Research, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia; {dagger} Laboratory of Viral Diseases, National Institute for Allergy and Infectious Diseases, Bethesda, MD 20892; and {ddagger} Peter MacCallum Cancer Institute, East Melbourne, Victoria, Australia

Immunodominance is a central feature of CD8+ T cell (TCD8+) responses to pathogens, transplants, and tumors. Determinants occupy a stable position in an immunodominance hierarchy ({alpha}-, {beta}-, etc.) defined by the frequencies of responding TCD8+. In this paper, we study the mechanistic basis for place-swapping between {alpha}- (acid polymerase (PA)224–233) and {beta}-determinants (nuclear protein 366–374) in primary vs secondary anti-influenza A virus (IAV) responses in mice. This phenomena was recently correlated with the inability of IAV-infected nondendritic cells (DCs) to generate PA224–233, and it was proposed that secondary TCD8+ are principally activated by IAV-infected epithelial cells, while primary TCD8+ are activated by IAV-infected DCs. In this study, we show that the inability of non-DCs to generate PA224–232 is relative rather than absolute, and that the preferential use of cross-priming in secondary anti-IAV responses can also account for the revised hierarchy. We further show that immunodomination of PA224–233-specific TCD8+ by nucleoprotein 366–374-specific TCD8+ plays a critical role in the phenomena, and that this is unlikely to be mediated by TCD8+ lysis of APCs or other cells.




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