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 (T_h1) 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 T_h1 cell responses after challenge/reexposure, with significantly lower proportions of vaginal IFN-γ⁺ CD4⁺ T cells. The impaired T_h1 cell responses in IL-17A^−/− mice coincided with smaller populations of IFN-γ⁺ CD4⁺ tissue resident memory T (T_RM) cells in the genital tract postimmunization. Taken together, these findings describe a novel role for IL-17A in regulating antiviral IFN-γ⁺ T_h1 cell immunity in the vaginal tract. This strategy could be exploited to enhance antiviral immunity following HSV-2 vaccination.

IMPORTANCE T helper type 1 (T_h1) 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 T_h1 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 (T_RM) cells in the genital tract postimmunization than did wild-type (WT) mice, which coincided with attenuated T_h1 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 T_h1 cell immunity and better overall protection.

众所周知，CD4 ⁺ T细胞产生的干扰素γ（IFN-γ）对于抵抗单纯疱疹病毒2（HSV-2）生殖器感染的抗病毒免疫至关重要。然而，尚未阐明CD4 ⁺ T细胞产生白介素17A（IL-17A）在HSV-2抗病毒免疫中的作用。在这里，我们证明IL-17A在增强女性生殖道（FGT）中的抗病毒T辅助型1（T _h 1）反应中起着重要作用，并且对于HSV-2疫苗给予的有效保护至关重要。尽管IL-17A在原发性生殖器HSV-2感染中没有发挥关键作用，但由于缺乏IL-17A缺陷（IL-17A ^-/-）和野生型（WT）C57BL / 6小鼠，这对于在激发/再暴露后介导抗病毒反应至关重要。与WT小鼠相比，IL-17A ^-/-小鼠（i）阴道内感染并再次暴露，或（ii）鼻内接种疫苗并经阴道内攻击表现出较差的结果。阴道内HSV-2再暴露或激发后，接种的IL-17A ^-/-小鼠的死亡率，病情严重程度，病毒释放量和阴道分泌物中促炎性细胞因子和趋化因子的水平明显更高。此外，IL-17A ^{- / -}小鼠的受损Ť _ħ质询/再暴露后1细胞应答，与阴道IFN-γ的显著较低比例的⁺ CD4⁺ T细胞。IL-17A ^-/-小鼠中受损的T _h 1细胞反应与免疫后生殖道中的IFN-γ ⁺ CD4 ⁺组织驻留记忆T（T _RM）细胞较小。总之，这些发现描述在调节抗病毒IFN-γ对IL-17A中的新作用⁺ Ť _ħ在阴道1细胞免疫。可以利用该策略来增强HSV-2疫苗接种后的抗病毒免疫性。

重要信息T辅助1型（T _h 1）免疫，特别是CD4 ⁺ T细胞产生的干扰素γ（IFN-γ），对于预防生殖器疱疹病毒（HSV-2）感染至关重要，增强这种反应可能有助于改善疾病结果。我们的研究表明，白细胞介素17A（IL-17A）在增强女性生殖道（FGT）中的抗病毒T _h 1反应中起着至关重要的作用。我们发现，在没有IL-17A的情况下，预先暴露和接种疫苗的小鼠显示出较差的疾病结果，并且无法克服HSV-2的再暴露/挑战。IL-17A缺陷小鼠（IL-17A ^-/-）的IFN-γ ⁺ CD4 ⁺组织固有记忆T（T与野生型（WT）小鼠相比，免疫后生殖道中的_RM）细胞与攻击后的T _h 1反应减弱有关。这对于开发针对HSV-2的有效疫苗具有重要意义，因为我们建议在生殖道中诱导IL-17A的策略可能会促进更有效的T _h 1细胞免疫和更好的整体保护。