E7-specific cytotoxic T cell tolerance in HPV-transgenic mice

The "high-risk" human papillomavirus type 16 (HPV 16) is associated with th e development of cervical cancer. Although the viral gene products E6 and E 7 are constitutively expressed in HPV 16-associated lesions and therefore a ppear as candidate antigens for a specific immune response, the immune syst em fails to produce an efficient defence against tumor outgrowth in affecte d patients. Keratinocytes are the natural target cells of HPV infection. To investigate the E7-specific immune response in vivo, we used transgenic mi ce expressing the oncogenes E6 and E7 of HPV 16 under the control of the ke ratin 10 promoter in the suprabasal layers of the epidermis. This expressio n pattern closely reflects the viral early gene transcription that is obser ved in low grade cervical intraepithelial lesions (CIN). The transgene prod uct E7 does not induce an immune response in these transgenic mice. However , upon vaccination anti-E7 antibodies were produced without causing signs o f autoimmune disease. In contrast, E7-specific cytotoxic T lymphocytes (CTL ) were not detected after immunization. From these results we conclude that in K10 HPV 16 E6/E7 transgenic mice the E7 transgene expression induces sp ecific immunological tolerance on the CTL level.