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Journal of Virology, May 2003, p. 5464-5474, Vol. 77, No. 9
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.9.5464-5474.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Human Papillomavirus Type 16 E7 Peptide-Directed CD8+ T Cells from Patients with Cervical Cancer Are Cross-Reactive with the Coronavirus NS2 Protein

Katja Nilges,1 Hanni Höhn,1 Henryk Pilch,2 Claudia Neukirch,1 Kirsten Freitag,1 P. J. Talbot,3 and Markus J. Maeurer1*

Department of Medical Microbiology, University of Mainz,1 Department of Gynecology and Obstetrics, Johannes Gutenberg University, Mainz, Germany,2 Human Health Research Center, INRS-Institut Armand Frappier, University of Quebec, Laval, Canada3

Received 9 August 2002/ Accepted 28 January 2003

Human papillomavirus type 16 (HPV16) E6 and E7 oncoproteins are required for cellular transformation and represent candidate targets for HPV-specific and major histocompatibility complex class I-restricted CD8+-T-cell responses in patients with cervical cancer. Recent evidence suggests that cross-reactivity represents the inherent nature of the T-cell repertoire. We identified HLA-A2 binding HPV16 E7 variant peptides from human, bacterial, or viral origin which are able to drive CD8+-T-cell responses directed against wild-type HPV16 E7 amino acid 11 to 19/20 (E711-19/20) epitope YMLDLQPET(T) in vitro. CD8+ T cells reacting to the HLA-A2-presented peptide from HPV16 E711-19(20) recognized also the HLA-A2 binding peptide TMLDIQPED (amino acids 52 to 60) from the human coronavirus OC43 NS2 gene product. Establishment of coronavirus NS2-specific, HLA-A2-restricted CD8+-T-cell clones and ex vivo analysis of HPV16 E7 specific T cells obtained by HLA-A2 tetramer-guided sorting from PBL or tumor-infiltrating lymphocytes obtained from patients with cervical cancer showed that cross-reactivity with HPV16 E711-19(20) and coronavirus NS252-60 represents a common feature of this antiviral immune response defined by cytokine production. Zero of 10 patients with carcinoma in situ neoplasia and 3 of 18 patients with cervical cancer showed >=0.1% HPV16 E7-reactive T cells in CD8+ peripheral blood lymphocytes. In vivo priming with HPV16 was confirmed in patients with cervical cancer or preinvasive HPV16-positive lesions using HLA-A2 tetramer complexes loaded with the E6-derived epitope KLPQLCTEL. In contrast, we could not detect E6-reactive T cells in healthy individuals. These data imply that the measurement of the HPV16 E711-19(20) CD8+-T-cell response may reflect cross-reactivity with a common pathogen and that variant peptides may be employed to drive an effective cellular immune response against HPV.

* Corresponding author. Mailing address: Dept. of Medical Microbiology, University of Mainz, Hochhaus Augustusplatz, 55101 Mainz, Germany. Phone: 49.(0)6131.39-33645. Fax: 49.(0)6131.39-35580. E-mail: maeurer{at}mail.uni-mainz.de.

Journal of Virology, May 2003, p. 5464-5474, Vol. 77, No. 9
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.9.5464-5474.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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