Novel Role for Interleukin-17 in Enhancing Type 1 Helper T Cell Immunity in the Female Genital Tract Following Mucosal Herpes Simplex Virus 2 Vaccination

J Virol. 2017 Nov 14;91(23):e01234-17. doi: 10.1128/JVI.01234-17. Print 2017 Dec 1.

Abstract

It is well established that interferon gamma (IFN-γ) production by CD4+ T cells is critical for antiviral immunity against herpes simplex virus 2 (HSV-2) genital infection. However, the role of interleukin-17A (IL-17A) production by CD4+ T cells in HSV-2 antiviral immunity is yet to be elucidated. Here we demonstrate that IL-17A plays an important role in enhancing antiviral T helper type 1 (Th1) responses in the female genital tract (FGT) and is essential for effective protection conferred by HSV-2 vaccination. While IL-17A did not play a critical role during primary genital HSV-2 infection, seen by lack of differences in susceptibility between IL-17A-deficient (IL-17A-/-) and wild-type (WT) C57BL/6 mice, it was critical for mediating antiviral responses after challenge/reexposure. Compared to WT mice, IL-17A-/- mice (i) infected intravaginally and reexposed or (ii) vaccinated intranasally and challenged intravaginally demonstrated poor outcomes. Following intravaginal HSV-2 reexposure or challenge, vaccinated IL-17A-/- mice had significantly higher mortality, greater disease severity, higher viral shedding, and higher levels of proinflammatory cytokines and chemokines in vaginal secretions. Furthermore, IL-17A-/- mice had impaired Th1 cell responses after challenge/reexposure, with significantly lower proportions of vaginal IFN-γ+ CD4+ T cells. The impaired Th1 cell responses in IL-17A-/- mice coincided with smaller populations of IFN-γ+ CD4+ tissue resident memory T (TRM) cells in the genital tract postimmunization. Taken together, these findings describe a novel role for IL-17A in regulating antiviral IFN-γ+ Th1 cell immunity in the vaginal tract. This strategy could be exploited to enhance antiviral immunity following HSV-2 vaccination.IMPORTANCE T helper type 1 (Th1) immunity, specifically interferon gamma (IFN-γ) production by CD4+ T cells, is critical for protection against genital herpesvirus (HSV-2) infection, and enhancing this response can potentially help improve disease outcomes. Our study demonstrated that interleukin-17A (IL-17A) plays an essential role in enhancing antiviral Th1 responses in the female genital tract (FGT). We found that in the absence of IL-17A, preexposed and vaccinated mice showed poor disease outcomes and were unable to overcome HSV-2 reexposure/challenge. IL-17A-deficient mice (IL-17A-/-) had smaller populations of IFN-γ+ CD4+ tissue resident memory T (TRM) cells in the genital tract postimmunization than did wild-type (WT) mice, which coincided with attenuated Th1 responses postchallenge. This has important implications for developing effective vaccines against HSV-2, as we propose that strategies inducing IL-17A in the genital tract may promote more effective Th1 cell immunity and better overall protection.

Keywords: CD4 T cell immunity; IL-17; genital tract immunity; herpes simplex virus; mucosal immunity; sexually transmitted diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Viral / biosynthesis
  • Antibodies, Viral / blood
  • CD4-Positive T-Lymphocytes / immunology
  • Chemokines / biosynthesis
  • Cytokines / biosynthesis
  • Female
  • Genitalia, Female / immunology*
  • Genitalia, Female / virology
  • Herpes Genitalis / immunology
  • Herpes Genitalis / prevention & control
  • Herpesvirus 2, Human / immunology*
  • Herpesvirus Vaccines / administration & dosage
  • Herpesvirus Vaccines / immunology*
  • Immunologic Memory
  • Interleukin-17 / deficiency
  • Interleukin-17 / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mucous Membrane / virology
  • Th1 Cells / immunology*
  • Vagina / immunology
  • Virus Shedding

Substances

  • Antibodies, Viral
  • Chemokines
  • Cytokines
  • Herpesvirus Vaccines
  • Interleukin-17