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Hidden Epitopes Emerge in Secondary Influenza Virus-Specific CD8⁺ T Cell Reponses¹

Paul G. Thomas^*, Scott A. Brown^*, Rachael Keating^*, Wen Yue^*, Melissa Y. Morris^*, Jenny So^*, Richard J. Webby and Peter C. Doherty^2,*

^* Department of Immunology and Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, TN 38105

Influenza A virus-specific CD8⁺ T cell responses in H2^b mice are characterized by reproducible hierarchies. Compensation by the D^bPB1-F2₆₂ epitope is apparent following infection with a variant H3N2 virus engineered to disrupt the prominent D^bNP₃₆₆ and D^bPA₂₂₄ epitopes (a double knockout or DKO). Analysis with a "triple" knockout (TKO) virus, which also compromises D^bPB1-F2₆₂, did not reveal further compensation to the known residual, minor, and predicted epitopes. However, infection with this deletion mutant apparently switched protective immunity to an alternative Ab-mediated pathway. As expected, TKO virus clearance was significantly delayed in Ab-deficient MHC class II^–/– and Ig^–/– mice, which were much more susceptible following primary, intranasal infection with the TKO, but not DKO, virus. CD8⁺ T cell compensation was detected in DKO, but not TKO, infection of Ig-deficient mice, suggestive of cooperation among CD8⁺ T cell responses. However, after priming with a TKO H1N1 mutant, MHC II^–/– mice survived secondary intranasal exposure to the comparable H3N2 TKO virus. Such prime/challenge experiments with the DKO and TKO viruses allowed the emergence of two previously unknown epitopes. The contrast between the absence of compensatory effect following primary exposure and the substantial clonal expansion after secondary challenge suggests that the key factor limiting the visibility of these "hidden" epitopes may be very low naive T cell precursor frequencies. Overall, these findings suggest that vaccine approaches using virus vectors to deliver an Ag may be optimized by disrupting key peptides in the normal CD8⁺ T cell response associated with common HLA types.

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 study was supported by National Institutes of Health Grants AI70251 (to P.D.), AI95357 (to R.W.), and AI065097 (to P.T.), a Burnet Award (to P.D.), and by private donations to the American Lebanese Syrian Associated Charities at St. Jude Children’s Research Hospital.

² Address correspondence and reprint requests to Dr. Peter C. Doherty, Department of Immunology, St. Jude Children’s Research Hospital, 332 N. Lauderdale Street, Memphis, TN, 38105. E-mail address: Peter.Doherty{at}stjude.org

³ Abbreviations used in this paper: NP, nucleoprotein; BAL, bronchoalveolar lavage; DC, dendritic cell; DKO, double knockout; F2, alternative reading frame of PB1 protein; ICS, intracellular cytokine staining; i.n., intranasal(ly); MDCK, Madin-Darby canine kidney; PA, viral acid polymerase; pMHCI, peptide-MHC I complex; QKO, quintuple knockout; TKO, triple knockout virus; WT, wild type.

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