CD4+ T cell immunity against the human papillomavirus-18 E6 transforming protein in healthy donors: Identification of promiscuous naturally processed epitopes

Abstract

Infection by 'high-risk' human papillomaviruses (HPV) is associated with the development of neoplastic lesions. HPV-18 is responsible for a very aggressive form of cancer and poor survival. As for other HPV types, immune surveillance has probably a role in the control of the infection. However, very little is known on HPV-18 immunogenicity. CD4+ T cells from 16 healthy donors were tested ex vivo for reactivity to synthetic peptides corresponding to 3 sequences on the HPV-18 E6 transforming protein predicted by bioinformatics as promiscuous HLA-DR ligands, and to the recombinant E6 protein. We found 3 donors with CD4+T cells that specifically proliferated in the presence of HPV-18 E6 antigens and produced IFN-γ in the presence of the E6 protein. We then propagated CD4+ T cell lines and clones from the responsive subjects to better characterize the recognized sequences. We show that E652-66 and E697-111 are indeed promiscuous and, most importantly, they contain naturally processed epitopes. Collectively, our data indicate that healthy donors may develop spontaneous CD4 immunity against HPV-18 E6 epitopes, thus strongly suggesting the potential for this protein to elicit in the host a natural productive immune response. © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.