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Intravaginal immunization with HPV vectors induces tissue-resident CD8+ T cell responses
Nicolas Çuburu, … , Douglas R. Lowy, John T. Schiller
Nicolas Çuburu, … , Douglas R. Lowy, John T. Schiller
Published November 12, 2012
Citation Information: J Clin Invest. 2012;122(12):4606-4620. https://doi.org/10.1172/JCI63287.
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Research Article Immunology Article has an altmetric score of 17

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

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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

Nicolas Çuburu, Barney S. Graham, Christopher B. Buck, Rhonda C. Kines, Yuk-Ying S. Pang, Patricia M. Day, Douglas R. Lowy, John T. Schiller

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Figure 11

HPV Ivag, but not Ad5 i.m., prime/boost immunization reduces viral titers in the cervicovaginal mucosa after vaginal challenge with recombinant M282–90–VV.

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HPV Ivag, but not Ad5 i.m., prime/boost immunization reduces viral titer...
Depo-Provera–treated mice were immunized with 5 × 107 IU HPV16MM2 Ivag or with 5 × 107 PFU Ad5-MM2 i.m., and 1 month later mice were immunized with 5 × 107 IU HPV45MM2 or Ad5-MM2 i.m., respectively. Two months after the last immunization, mice were challenged Ivag with 1 × 107 PFU of recombinant M282–90–VV. Three days after challenge, vaginal tissue was collected, and recombinant VV titers were determined by plaque assays. Results are expressed as PFU per vagina for individual mice (symbols) and geometric mean (horizontal bars). Data are representative of 3 experiments (*P < 0.05, **P < 0.01, Kruskal-Wallis/Dunn’s test).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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