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

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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.

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