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

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

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 1

Ivag heterologous prime/boost immunization regimen overcomes type-specific antibody neutralization and enhances CD8+ T cell response in the genital tract.

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Ivag heterologous prime/boost immunization regimen overcomes type-specif...
(A) Depo-Provera–treated BALB/c mice (n = 5/group) were inoculated Ivag with 5 × 107 IU HPV16 PsV expressing luciferase (16Luc) or sham treated. One month after initial 16Luc PsV inoculation, mice were challenged Ivag with 5 × 107 IU 16Luc or HPV45 PsV expressing luciferase (45Luc). In vivo luciferase expression was measured 2 days after Ivag challenge and is expressed as mean luminescence in photons per second + SD (**P < 0.01, Mann Whitney U test). (B) Depo-Provera–treated mice were immunized Ivag with 5 × 107 IU HPV PsV expressing the RSV fusion protein M/M2. For the single immunization regimen, mice were immunized with 5 × 107 IU HPV16MM2 PsV, and for the prime/boost regimen, they were immunized with 5 × 107 IU HPV16MM2; 1 month later the primed animals were immunized with 5 × 107 IU HPV45MM2. Two weeks after the final immunization, vaginal cell suspensions were analyzed by flow cytometry for the presence of KdM282-tetramer+CD8+ T lymphocytes. Data are expressed as the mean of the total number of cells per organ + SD (*P < 0.05, **P < 0.01, Kruskal-Wallis/Dunn’s test).