title: Disease-stage variance in functional CD4(+) T-cell responses against novel pan-human leukocyte antigen-D region presented human papillomavirus-16 E7 epitopes.
abstract: Given the anticipated clinical importance of helper and regulatory CD4(+) T cells reactive against human papillomavirus-16 E7 in the cervical carcinoma setting, we performed this study to identify novel E7-derived T helper (Th) epitopes and to characterize functional anti-E7 Th responses in normal donors and patients with cervical intraepithelial neoplasia I-III or cervical cancer. Candidate pan-HLA-DR (D region) binding peptides were identified and synthesized based on results obtained using a predictive computer algorithm, then applied in short-term in vitro T-cell sensitization assays. Using IFN-gamma/IL-5 (interleukin 5) enzyme-linked immunospot assays as readouts for Th1-type and Th2-type CD4(+) T-cell responses, respectively, we identified three E7-derived T helper epitopes (E7(1-12), E7(48-62), and E7(62-75)), two of which are novel. Normal donor CD4(+) T cells failed to react against these E7 peptides, whereas patients with premalignant cervical intraepithelial neoplasia I-III lesions displayed preferential Th1-type responses against all three E7 epitopes. Th1-type responses were still observed to the E7(48-62) but not to the E7(1-12) and E7(62-75) peptides in cancer patients, where these latter two epitopes evoked Th2-type responses. Notably all responders to the E7(1-12) and E7(62-75) peptides expressed the HLA-DR4 or -DR15 alleles, whereas all responders to the E7(48-62) peptide failed to express the HLA-DR4 allele. Our results are consistent with a model in which cervical cancer progression is linked to an undesirable Th1- to Th2-type shift in functional CD4(+) T cell responses to two novel E7-derived epitopes. These peptides may prove important in vaccines to promote and maintain protective Th1-type antihuman papillomavirus immunity and in the immune monitoring of treated patients harboring HPV-16(+) malignancies.
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Dominic E
authors.initials: DE
authors.lastname: Warrino
authors.forename: Walter C
authors.initials: WC
authors.lastname: Olson
authors.forename: William T
authors.initials: WT
authors.lastname: Knapp
authors.forename: Meera I
authors.initials: MI
authors.lastname: Scarrow
authors.forename: Lori J
authors.initials: LJ
authors.lastname: D'Ambrosio-Brennan
authors.forename: Richard S
authors.initials: RS
authors.lastname: Guido
authors.forename: Robert P
authors.initials: RP
authors.lastname: Edwards
authors.forename: W Martin
authors.initials: WM
authors.lastname: Kast
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Storkus
mesh_terms: D000328:Adult; D000483:Alleles; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D003713:Dendritic Cells / Q000378:metabolism / Q000821:virology; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry*; D005260:Female; D005814:Genes, Viral; D005838:Genotype; D015804:HLA-DR4 Antigen / Q000737:chemistry / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D015848:Interleukin-5 / Q000737:chemistry / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D008875:Middle Aged; D009856:Oncogene Proteins, Viral / Q000737:chemistry* / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D017434:Protein Structure, Tertiary; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018417:Th1 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000821:virology*
chemical_list: D000939:Epitopes; D015804:HLA-DR4 Antigen; D015848:Interleukin-5; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D010455:Peptides; C059731:oncogene protein E7, Human papillomavirus type 16; D007371:Interferon-gamma