title: Vaginal memory T cells induced by intranasal vaccination are critical for protective T cell recruitment and prevention of genital HSV-2 disease.
abstract: Protective immunity against genital pathogens causing chronic infections, such as herpes simplex virus 2 (HSV-2) or human immunodeficiency virus, requires the induction of cell-mediated immune responses locally in the genital tract. Intranasal immunization with a thymidine kinase-deficient (TK(-)) mutant of HSV-2 effectively induces HSV-2-specific gamma interferon (IFN-γ)-secreting memory T cell production and protective immunity against intravaginal challenge with wild-type HSV-2. However, the precise mechanism by which intranasal immunization induces protective immunity in the distant genital mucosa more effectively than does systemic immunization is unknown. Here, we showed that intranasal immunization with live HSV-2 TK(-) induced the production of effector T cells and their migration to, and retention in, the vaginal mucosa, whereas systemic vaccination barely established a local effector T cell pool, even when it induced the production of circulating memory T cells in the systemic compartment. The long-lasting HSV-2-specific local effector T cells induced by intranasal vaccination provided superior protection against intravaginal wild-type HSV-2 challenge by starting viral clearance at the entry site earlier than with intraperitoneal immunization. Intranasal immunization is an effective strategy for eliciting high levels of cell-mediated protection of the genital tract by providing long-lasting antigen (Ag)-specific local effector T cells without introducing topical infection or inflammation.
  
  
  OBJECTIVE
  Intranasal (i.n.) vaccines against sexually transmitted diseases that are caused by viruses such as herpes simplex virus 2 (HSV-2) have long been in development, but no vaccine candidate is currently available. Understanding the cellular mechanisms of immune responses in a distant vaginal mucosa induced by i.n. immunization with HSV-2 will contribute to designing such a vaccine. Our study demonstrated that i.n. immunization with an attenuated strain of HSV-2 generated long-lasting IFN-γ-secreting T cells in vaginal mucosa more effectively than systemic immunization. We found that these vaginal effector memory T cells are critical for the early stage of viral clearance at natural infection sites and prevent severe vaginal inflammation and herpes encephalitis.
authors.affiliation: Division of Mucosal Immunology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Ayuko
authors.initials: A
authors.lastname: Sato
authors.affiliation: Division of Mucosal Immunology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan Department of Medical Genome Science, Graduate School of Frontier Science, University of Tokyo, Kashiwa, Chiba, Japan.
authors.forename: Aldina
authors.initials: A
authors.lastname: Suwanto
authors.affiliation: Division of Mucosal Immunology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Manami
authors.initials: M
authors.lastname: Okabe
authors.affiliation: Division of Mucosal Immunology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan International Research and Development Center for Mucosal Vaccines, Institute of Medical Science, University of Tokyo, Tokyo, Japan Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Sato
authors.affiliation: Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Nochi
authors.affiliation: Division of Molecular Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan Division of Viral Infection, Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan Nippon Institute for Biological Science, Ome, Tokyo, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Imai
authors.affiliation: Division of Molecular Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan Division of Viral Infection, Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Koyanagi
authors.affiliation: Division of Mucosal Immunology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan International Research and Development Center for Mucosal Vaccines, Institute of Medical Science, University of Tokyo, Tokyo, Japan Laboratory of Vaccine Materials, National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Kunisawa
authors.affiliation: Division of Molecular Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan Division of Viral Infection, Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kawaguchi
authors.affiliation: Division of Mucosal Immunology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan Department of Medical Genome Science, Graduate School of Frontier Science, University of Tokyo, Kashiwa, Chiba, Japan International Research and Development Center for Mucosal Vaccines, Institute of Medical Science, University of Tokyo, Tokyo, Japan Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama, Japan kiyono@ims.u-tokyo.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyono
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D005260:Female; D006558:Herpes Genitalis / Q000276:immunology / Q000517:prevention & control*; D018258:Herpesvirus 2, Human / Q000276:immunology*; D022283:Herpesvirus Vaccines / Q000008:administration & dosage / Q000276:immunology*; D018928:Immunity, Mucosal; D007156:Immunologic Memory; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology*; D014621:Vagina / Q000276:immunology*
chemical_list: D022283:Herpesvirus Vaccines