Intravaginal immunization with HPV vectors induces tissue-resident CD8+ T cell responses

J Clin Invest. 2012 Dec;122(12):4606-20. doi: 10.1172/JCI63287. Epub 2012 Nov 12.


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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Administration, Intravaginal
  • Animals
  • Antigens, Viral / biosynthesis
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / physiology
  • Cell Proliferation
  • Cytotoxicity, Immunologic
  • Female
  • Genes, Reporter
  • Genetic Vectors
  • HEK293 Cells
  • Human papillomavirus 16 / genetics*
  • Human papillomavirus 16 / immunology
  • Humans
  • Immunization, Secondary
  • Immunologic Memory
  • Interferon-gamma / metabolism
  • Luciferases, Firefly / biosynthesis
  • Luciferases, Firefly / genetics
  • Lymph Nodes / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mucous Membrane / immunology
  • Mucous Membrane / virology
  • Papillomavirus Vaccines / administration & dosage*
  • Papillomavirus Vaccines / genetics
  • Respiratory Syncytial Virus Infections / prevention & control
  • Respiratory Syncytial Viruses / immunology
  • Spleen / immunology
  • Statistics, Nonparametric
  • Tumor Necrosis Factor-alpha / metabolism
  • Vaccination*
  • Vaccines, Synthetic / administration & dosage
  • Vaccines, Synthetic / genetics
  • Vaccinia virus / genetics
  • Vaccinia virus / immunology
  • Vagina / immunology
  • Vagina / virology


  • Antigens, Viral
  • Papillomavirus Vaccines
  • Tumor Necrosis Factor-alpha
  • Vaccines, Synthetic
  • Interferon-gamma
  • Luciferases, Firefly