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Immunoproteasome Subunit Deficiencies Impact Differentially on Two Immunodominant Influenza Virus-Specific CD8⁺ T Cell Responses¹

Ken C. Pang^*, Megan T. Sanders^*, John J. Monaco, Peter C. Doherty, Stephen J. Turner and Weisan Chen^2,*

^* T Cell Laboratory, Melbourne Centre for Clinical Sciences, Ludwig Institute for Cancer Research, Austin Health, Heidelberg, Australia; Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, Cincinnati, OH 45267; and Department of Microbiology and Immunology, University of Melbourne, Parkville, Australia

Primary CD8⁺ T cell (T_CD8⁺) responses to viruses are directed toward multiple Ags and shaped by both the level of Ag presentation and the underlying Ag-specific T_CD8⁺ repertoire. The relative importance of these factors in deciding the hierarchy of T_CD8⁺ responses and how they are influenced by the immunoproteasome are not well understood. Using an influenza infection model in mice deficient in various immunoproteasome subunits, we observe that Ag presentation and T_CD8⁺ repertoire are altered in an epitope-specific and immunoproteasome subunit-dependent manner. More importantly, we find that the level of Ag presentation and the extent of the underlying repertoire can work either alone or in concert to determine definitively the magnitude of the individual T_CD8⁺ responses and hence the overall T_CD8⁺ hierarchy. Together, these results provide a clearer understanding of how immunodominance hierarchies are established.

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 in part by National Health and Medical Research Council Project Grant 234710 and a project grant from the Anti-Cancer Council of Victoria. W.C. is a Senior International Fellow supported by the Wellcome Trust (066646/Z/01/Z). K.P. is supported by National Health and Medical Research Council Postgraduate Research Scholarship 234711.

² Address correspondence and reprint requests to Dr. Weisan Chen, T Cell Laboratory, Melbourne Centre for Clinical Sciences, Ludwig Institute for Cancer Research, Austin Health, Heidelberg, Victoria 3084, Australia. E-mail address: weisan.chen{at}ludwig.edu.au

³ Abbreviations used in this paper: T_CD8⁺, CD8⁺ T cell; NP, nucleoprotein; NP366, NP_366–374; PA, acidic polymerase; PA224, PA_224–233; PB1F2, PB1F2_62–70; BMDC, bone marrow-derived dendritic cell; ICS, intracellular cytokine staining; NA, neuraminidase; BFA, brefeldin A; PR8, A/Puerto Rico/8/34 (HINI) influenza virus; NA, neuraminidase.

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