title: Identification of the murine H-2D(b) and human HLA-A*0201 MHC class I-restricted HPV6 E7-specific cytotoxic T lymphocyte epitopes.
abstract: Recurrent respiratory papillomatosis is caused by human papillomavirus (HPV) infection, most commonly types 6 (HPV-6) and 11 (HPV-11). Due to failed host immune responses, HPV is unable to be cleared from the host, resulting in recurrent growth of HPV-related lesions that can obstruct the lumen of the airway within the upper aerodigestive tract. In our murine model, the HPV-6b and HPV-11 E7 antigens are not innately immunogenic. In order to enhance the host immune responses against the HPV E7 antigen, we linked calreticulin (CRT) to HPV-6b E7 and found that vaccinating C57BL/6 mice with the HPV-6b CRT/E7 DNA vaccine is able to induce a CD8+ T cell response that recognizes an H-2D(b)-restricted E7aa21-29 epitope. Additionally, vaccination of HLA-A*0201 transgenic mice with HPV-6b CRT/E7 DNA generated a CD8+ T cell response against the E7aa82-90 epitope that was not observed in the wild-type C57BL/6 mice, indicating this T cell response is restricted to HLA-A*0201. In vivo cytotoxic T cell killing assays demonstrated that the vaccine-induced CD8+ T cells are able to efficiently kill target cells. Interestingly, the H-2D(b)-restricted E7aa21-29 sequence and the HLA-A*0201-restricted E7aa82-90 sequence are conserved between HPV-6b and HPV-11 and may represent shared immunogenic epitopes. The identification of the HPV-6b/HPV-11 CD8+ T cell epitopes facilitates the evaluation of various immunomodulatory strategies in preclinical models. More importantly, the identified HLA-A*0201-restricted T cell epitope may serve as a peptide vaccination strategy, as well as facilitate the monitoring of vaccine-induced HPV-specific immunologic responses in future human clinical trials.
authors.affiliation: Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Shiwen
authors.initials: S
authors.lastname: Peng
authors.affiliation: Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Austin
authors.initials: A
authors.lastname: Mattox
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Simon R
authors.initials: SR
authors.lastname: Best
authors.affiliation: Department of Surgery, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA.
authors.forename: Anca M
authors.initials: AM
authors.lastname: Barbu
authors.affiliation: Department of Surgery, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Burns
authors.affiliation: Department of Surgery, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA.
authors.forename: Belinda
authors.initials: B
authors.lastname: Akpeng
authors.affiliation: Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Jeang
authors.affiliation: Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Yang
authors.affiliation: Department of Surgery, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Ishida
authors.affiliation: Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.|Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Hung
authors.affiliation: Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.|Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.|Department of Obstetrics and Gynecology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.|Department of Molecular Microbiology and Immunology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Tzyy-Choou
authors.initials: TC
authors.lastname: Wu
authors.affiliation: Department of Surgery, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. sara.pai@mgh.harvard.edu.
authors.forename: Sara I
authors.initials: SI
authors.lastname: Pai
mesh_terms: D000818:Animals; D037282:Calreticulin / Q000494:pharmacology; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology*; D064532:Histocompatibility Antigen H-2D / Q000276:immunology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009856:Oncogene Proteins, Viral / Q000276:immunology*; D053918:Papillomavirus Vaccines / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology
chemical_list: D037282:Calreticulin; D018984:Epitopes, T-Lymphocyte; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D064532:Histocompatibility Antigen H-2D; D009856:Oncogene Proteins, Viral; D053918:Papillomavirus Vaccines; D019444:Vaccines, DNA; C062495:oncogene protein E7, Human papillomavirus type 6
keywords: Human papillomavirus; Immunotherapy; MHC class I; Recurrent respiratory papillomatosis; T cell epitope; Vaccine