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Addition of a Prominent Epitope Affects Influenza A Virus-Specific CD8⁺ T Cell Immunodominance Hierarchies When Antigen Is Limiting¹

Misty Rayna Jenkins^*, Richard Webby, Peter C. Doherty^*, and Stephen J. Turner^2,*

^* Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia; Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, TN 38105; and Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105

A reverse genetics strategy was used to insert the OVA peptide (amino acid sequence SIINFEKL; OVA_257–264) into the neuraminidase stalk of both the A/PR8 (H1N1) and A/HKx31 (H3N2) influenza A viruses. Initial characterization determined that K^bOVA₂₅₇ is presented on targets infected with PR8-OVA and HK-OVA without significantly altering D^b nucleoprotein (NP)₃₆₆ presentation. There were similar levels of K^bOVA₂₅₇- and D^bNP₃₆₆-specific CTL expansion following both primary and secondary intranasal challenge. Interestingly, while variable, the presence of the immunodominant K^bOVA₂₅₇-specific response resulted in diminished D^b acidic polymerase₂₂₄- and K^b basic polymerase subunit 1₇₀₃-, but not D^bNP₃₆₆-specific responses and didn’t alter endogenous influenza A virus-specific immunodominance hierarchies. However, challenging PR8-OVA-primed mice with HK-OVA via the i.p. route, and thereby limiting Ag dose, led to a reduction in the magnitude of all the influenza A virus-specific responses measured. A similar reduction in CTL response to native epitopes was also seen following primary respiratory HK-OVA infection of mice that received substantial numbers of K^bOVA₂₅₇-specific TCR transgenic T cells. Thus, during the course of infection, the generation of individual virus-specific CTL responses is independently regulated. However, in cases in which Ag is limiting, or high precursor frequency, the presence of immunodominant CTL responses can impact on the magnitude of other specific populations. Therefore, depending on both the size of the T cell precursor pool and the mode of Ag presentation, the addition of a major epitope can diminish the size of endogenous, influenza-specific CD8⁺ T cell responses, although never to the point that these are totally compromised.

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 an Australian Postgraduate Scholarship awarded to M.R.J.; a National Health and Medical Research Council Burnet Fellowship awarded to P.C.D.; a National Health and Medical Research Council RD Wright Fellowship awarded to S.J.T.; Science Technology, Innovation funds from the Government of Victoria, Australia; and U.S. Public Health Service Grants AI29579 and ALSAC at St. Jude Children’s Research Hospital.

² Address correspondence and reprint requests to Dr. Stephen J. Turner, Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia. E-mail address: sjturn{at}unimelb.edu.au

³ Abbreviations used in this paper: Tg, transgenic; BAL, bronchoalveolar lavage; i.n., intranasal; MDCK, Madin-Darby canine kidney; NA, neuraminidase; NP, nucleoprotein; PA, acidic polymerase; PB1, basic polymerase subunit 1.

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