IMMUNOLOGICAL IGNORANCE OF AN E7-ENCODED CYTOLYTIC T-LYMPHOCYTE EPITOPE IN TRANSGENIC MICE EXPRESSING THE E7 AND E6 ONCOGENES OF HUMAN PAPILLOMAVIRUS TYPE-16

Certain human papillomaviruses (HPV) have been implicated in the etiol ogy of cervical malignancies, and the E7 and E6 gene products of HPV t ype 16 are frequently expressed in these lesions, However, cytolytic T -lymphocyte (CTL)-mediated responses to HPV are rarely detectable in p atients with cervical cancer. To examine whether the T-cell response i s deficient during the HPV-induced transformation, we produced lines o f transgenic (Tg) mice that expressed the E6 and E7 oncogenes in kerat inized epithelia, The mice developed severe hypertrophy of all keratin ized epithelia, but no malignancies were observed. Although epithelial cells from Tg mice could present at least an E7-encoded CTL epitope ( E7 49-57), CTLs from these mice were neither primed to nor made tolera nt of this epitope, No quantitative or qualitative differences were se en in the CTL responses of the Tg mice compared to those of their litt ermates following immunization with the peptide E7 49-57, Immunization of Tg mice with the E7 49-57 peptide protected them against a subcuta neous challenge with tumor cells expressing a transfected E7 gene, yet the skin was unaffected, although the cultured skin epithelial cells from Tg mice expressed E7, Our results suggest that the Tg mice were i mmunologically ignorant of HPV oncoproteins with respect to a CTL resp onse and that a similar type of ignorance may explain why HPV-associat ed cervical cancer cells can escape immunological destruction.