Given the anticipated clinical importance of helper and regulatory CD4؉ T cells reactive against human papillomavirus-16 E7 in the cervical carcinoma setting, we performed this study to identify novel E7-derived T helper (Th) epitopes and to characterize functional anti-E7 Th responses in normal donors and patients with cervical intraepithelial neoplasia I-III or cervical cancer.Candidate pan-HLA-DR (D region) binding peptides were identified and synthesized based on results obtained using a predictive computer algorithm, then applied in short-term in vitro T-cell sensitization assays. Using IFN-␥/ IL-5 (interleukin 5) enzyme-linked immunospot assays as readouts for Th1-type and Th2-type CD4؉ T-cell responses, respectively, we identified three E7-derived T helper epitopes (E7 1-12 , E7 48 -62 , and E7 62-75 ), two of which are novel.Normal donor CD4 ؉ T cells failed to react against these E7 peptides, whereas patients with premalignant cervical intraepithelial neoplasia I-III lesions displayed preferential Th1-type responses against all three E7 epitopes. Th1-type responses were still observed to the E7 48 -62 but not to the E7 1-12 and E7 62-75 peptides in cancer patients, where these latter two epitopes evoked Th2-type responses. Notably all responders to the E7 1-12 and E7 62-75 peptides expressed the HLA-DR4 or -DR15 alleles, whereas all responders to the E7 48 -62 peptide failed to express the HLA-DR4 allele.Our results are consistent with a model in which cervical cancer progression is linked to an undesirable Th1-to Th2-type shift in functional CD4 ؉ T cell responses to two novel E7-derived epitopes. These peptides may prove important in vaccines to promote and maintain protective Th1-type antihuman papillomavirus immunity and in the immune monitoring of treated patients harboring HPV-16 ؉ malignancies.

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