Identification of HLA-DR1- and HLA-DR15-restricted human papillomavirus type 16 (HPV16) and HPV18 E6 epitopes recognized by CD4+ T cells from healthy young women.

Human papillomavirus (HPV) infection, particularly with types 16 and 18, is causally associated with the development of cervical cancer. Prophylactic vaccines against HPV have recently been licensed and have the primary aim of protecting children against future HPV infection and cervical cancer. However, these vaccines are unlikely to be effective in women with pre-existing HPV infection and disease. Previous studies have suggested that HPV16 E6-specific CD4+ T cells play a role in controlling viral infection; however, the epitopes recognized by such T-cells have not been defined. In this study, we analysed T-cell responses against HPV16 and 18 in ten healthy young women in an age group (21-31) with a high prevalence of HPV infection and clearance. Five individuals made HPV E6 responses, from which five candidate T-cell epitopes (three HPV16 E6 and two HPV18 E6) were identified. More detailed characterization of epitopes from HPV16 E6(127-141) and HPV18 E6(43-57) revealed HLA-DRB1*01 and HLA-DRB1*15 restriction, respectively. Furthermore, generation of a T-cell line against HPV16 E6(127-141) demonstrated that this epitope could be presented after endogenous processing of soluble HPV16 E6 protein. Overall we demonstrate a powerful approach for defining novel CD4+ T-cell epitopes from two oncogenic HPV types. This approach could be applied to study populations in developing countries with a high incidence of cervical cancer. Such epitopes could provide a more precise way of investigating the role of natural and vaccine-induced T-cell responses against HPV in blood and at sites of disease.