title: 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-gamma 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 E6(52-66) and E6(97-111) 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.
authors.affiliation: Laboratory of Tumor Immunology, DIBIT, Scientific Institute H. San Raffaele, Milan, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Facchinetti
authors.forename: Samantha
authors.initials: S
authors.lastname: Seresini
authors.forename: Renato
authors.initials: R
authors.lastname: Longhi
authors.forename: Claudio
authors.initials: C
authors.lastname: Garavaglia
authors.forename: Giulia
authors.initials: G
authors.lastname: Casorati
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Protti
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001782:Blood Donors; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology*; D009858:Oncogenic Viruses / Q000276:immunology; D027383:Papillomaviridae / Q000276:immunology; D030361:Papillomavirus Infections / Q000453:epidemiology / Q000276:immunology*; D015995:Prevalence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014412:Tumor Virus Infections / Q000453:epidemiology / Q000276:immunology*
chemical_list: D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; D018984:Epitopes, T-Lymphocyte; D009856:Oncogene Proteins, Viral