Document Detail


Intravaginal immunization with HPV vectors induces tissue-resident CD8+ T cell responses.
MedLine Citation:
PMID:  23143305     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural     Date:  2012-11-12
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  122     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-03     Completed Date:  2013-02-04     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4606-20     Citation Subset:  AIM; IM    
Affiliation:
Laboratory of Cellular Oncology, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
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MeSH Terms
Descriptor/Qualifier:
Administration, Intravaginal
Animals
Antigens, Viral / biosynthesis
CD8-Positive T-Lymphocytes / immunology*,  metabolism,  physiology
Cell Proliferation
Cytotoxicity, Immunologic
Female
Genes, Reporter
Genetic Vectors
HEK293 Cells
Human papillomavirus 16 / genetics*,  immunology
Humans
Immunization, Secondary
Immunologic Memory
Interferon-gamma / metabolism
Luciferases, Firefly / biosynthesis,  genetics
Lymph Nodes / immunology
Mice
Mice, Inbred BALB C
Mucous Membrane / immunology,  virology
Papillomavirus Vaccines / administration & dosage*,  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,  genetics
Vaccinia virus / genetics,  immunology
Vagina / immunology,  virology
Chemical
Reg. No./Substance:
0/Antigens, Viral; 0/Papillomavirus Vaccines; 0/Tumor Necrosis Factor-alpha; 0/Vaccines, Synthetic; 82115-62-6/Interferon-gamma; EC 1.13.12.7/Luciferases, Firefly
Comments/Corrections

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