title: Intravaginal immunization with HPV vectors induces tissue-resident CD8+ T cell responses.
abstract: The induction of persistent intraepithelial CD8+ T cell responses may be key to the development of vaccines against mucosally transmitted pathogens, particularly for sexually transmitted diseases. Here we investigated CD8+ T cell responses in the female mouse cervicovaginal mucosa after intravaginal immunization with human papillomavirus vectors (HPV pseudoviruses) that transiently expressed a model antigen, respiratory syncytial virus (RSV) M/M2, in cervicovaginal keratinocytes. An HPV intravaginal prime/boost with different HPV serotypes induced 10-fold more cervicovaginal antigen-specific CD8+ T cells than priming alone. Antigen-specific T cell numbers decreased only 2-fold after 6 months. Most genital antigen-specific CD8+ T cells were intra- or subepithelial, expressed αE-integrin CD103, produced IFN-γ and TNF-α, and displayed in vivo cytotoxicity. Using a sphingosine-1-phosphate analog (FTY720), we found that the primed CD8+ T cells proliferated in the cervicovaginal mucosa upon HPV intravaginal boost. Intravaginal HPV prime/boost reduced cervicovaginal viral titers 1,000-fold after intravaginal challenge with vaccinia virus expressing the CD8 epitope M2. In contrast, intramuscular prime/boost with an adenovirus type 5 vector induced a higher level of systemic CD8+ T cells but failed to induce intraepithelial CD103+CD8+ T cells or protect against recombinant vaccinia vaginal challenge. Thus, HPV vectors are attractive gene-delivery platforms for inducing durable intraepithelial cervicovaginal CD8+ T cell responses by promoting local proliferation and retention of primed antigen-specific CD8+ T cells.
authors.affiliation: Laboratory of Cellular Oncology, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Çuburu
authors.forename: Barney S
authors.initials: BS
authors.lastname: Graham
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Buck
authors.forename: Rhonda C
authors.initials: RC
authors.lastname: Kines
authors.forename: Yuk-Ying S
authors.initials: YY
authors.lastname: Pang
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Day
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Lowy
authors.forename: John T
authors.initials: JT
authors.lastname: Schiller
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D000956:Antigens, Viral / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic; D005260:Female; D017930:Genes, Reporter; D005822:Genetic Vectors; D057809:HEK293 Cells; D052162:Human papillomavirus 16 / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007117:Immunization, Secondary; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000378:metabolism; D049409:Luciferases, Firefly / Q000096:biosynthesis / Q000235:genetics; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009092:Mucous Membrane / Q000276:immunology / Q000821:virology; D053918:Papillomavirus Vaccines / Q000008:administration & dosage* / Q000235:genetics; D018357:Respiratory Syncytial Virus Infections / Q000517:prevention & control; D012136:Respiratory Syncytial Viruses / Q000276:immunology; D013154:Spleen / Q000276:immunology; D018709:Statistics, Nonparametric; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014611:Vaccination; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology; D014621:Vagina / Q000276:immunology / Q000821:virology
chemical_list: D000956:Antigens, Viral; D053918:Papillomavirus Vaccines; D014409:Tumor Necrosis Factor-alpha; D014614:Vaccines, Synthetic; D007371:Interferon-gamma; D049409:Luciferases, Firefly