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

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 alpha(E)-integrin CD103, produced IFN-gamma and TNF-alpha, and displayed in vivo cytotoxicity. Using a sphingosine-l-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.