Association of HPV16 E7-specific T cell responses in cervical lymphocytes and peripheral blood with regression of high-grade cervical intraepithelial neoplasia lesions

Abstract

Abstract Background While human papillomavirus (HPV)-specific T cell responses are believed to contribute to regression of HPV-associated cervical neoplasia, their role has not been fully elucidated. We investigated HPV16 E7-specific T cell responses in the cervix and peripheral blood and their association with pathological outcomes in cervical intraepithelial neoplasia grade 2 (CIN2). Methods HPV16 E7-specific T cell responses in cervical lymphocytes (CxLs) and peripheral blood mononuclear cells (PBMCs) were quantified using overlapping peptide (OLP) pools of E7 in 38 subjects with HPV16-positive CIN2 with defined pathological outcomes. Breadth and HLA restriction of these responses were assessed using single OLPs on in vitro-expanded PBMCs. Results HPV16 E7-specific T cell responses were detected in over 30% of CxL samples but rarely detected in PBMCs unless expanded in vitro. Higher magnitudes of E7-stimulated responses in CxLs, along with elevated non-specific background responses, were associated with pathological regression of CIN2 lesions. The E7-specific T cell responses in expanded PBMCs varied in breadth among subjects and were mediated by both CD4+ and CD8+ T cells with diverse HLA restrictions. Importantly, response breadth was significantly greater in subjects with lesion regression. Conclusions HPV-specific T cell responses are preferentially localized at the site of infection and maintained at low frequencies in peripheral blood. The magnitude of local E7-stimulated response in CxLs and the breadth of E7-specific responses in expanded PBMCs were associated with pathological regression of CIN2. These associations support a potential role for E7-specific T cell responses in the regression of HPV-related cervical neoplasia.