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

The "high-risk" human papillomavirus type 16 (HPV 16) is associated with the development of cervical cancer. Although the viral gene products E6 and E7 are constitutively expressed in HPV 16-associated lesions and therefore appear as candidate antigens for a specific immune response, the immune system fails to produce an efficient defence against tumor outgrowth in affected patients. Keratinocytes are the natural target cells of HPV infection. To investigate the E7-specific immune response in vivo, we used transgenic mice expressing the oncogenes E6 and E7 of HPV 16 under the control of the keratin 10 promoter in the suprabasal layers of the epidermis. This expression pattern closely reflects the viral early gene transcription that is observed in low grade cervical intraepithelial lesions (CIN). The transgene product E7 does not induce an immune response in these transgenic mice. However, upon vaccination anti-E7 antibodies were produced without causing signs of 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 specific immunological tolerance on the CTL level.