Bagri Puja, Anipindi Varun C, Nguyen Philip V, Vitali Danielle, Stämpfli Martin R, Kaushic Charu
McMaster Immunology and Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
McMaster Immunology and Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
J Virol. 2017 Nov 14;91(23). doi: 10.1128/JVI.01234-17. Print 2017 Dec 1.
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 (T1) 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 () and wild-type (WT) C57BL/6 mice, it was critical for mediating antiviral responses after challenge/reexposure. Compared to WT mice, mice (i) infected intravaginally and reexposed or (ii) vaccinated intranasally and challenged intravaginally demonstrated poor outcomes. Following intravaginal HSV-2 reexposure or challenge, vaccinated mice had significantly higher mortality, greater disease severity, higher viral shedding, and higher levels of proinflammatory cytokines and chemokines in vaginal secretions. Furthermore, mice had impaired T1 cell responses after challenge/reexposure, with significantly lower proportions of vaginal IFN-γ CD4 T cells. The impaired T1 cell responses in mice coincided with smaller populations of IFN-γ CD4 tissue resident memory T (T) cells in the genital tract postimmunization. Taken together, these findings describe a novel role for IL-17A in regulating antiviral IFN-γ T1 cell immunity in the vaginal tract. This strategy could be exploited to enhance antiviral immunity following HSV-2 vaccination. T helper type 1 (T1) 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 T1 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 () had smaller populations of IFN-γ CD4 tissue resident memory T (T) cells in the genital tract postimmunization than did wild-type (WT) mice, which coincided with attenuated T1 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 T1 cell immunity and better overall protection.
众所周知，CD4 T细胞产生的干扰素γ（IFN-γ）对于抗单纯疱疹病毒2型（HSV-2）生殖器感染的抗病毒免疫至关重要。然而，CD4 T细胞产生的白细胞介素-17A（IL-17A）在HSV-2抗病毒免疫中的作用尚待阐明。在此，我们证明IL-17A在增强女性生殖道（FGT）中的抗病毒1型辅助性T细胞（T1）反应中起重要作用，并且对于HSV-2疫苗接种所提供的有效保护至关重要。虽然在原发性生殖器HSV-2感染期间IL-17A未发挥关键作用，这从IL-17A缺陷型（）和野生型（WT）C57BL/6小鼠之间易感性缺乏差异可以看出，但它对于激发/再次接触后的抗病毒反应至关重要。与WT小鼠相比，（i）经阴道感染并再次接触或（ii）经鼻接种并经阴道激发的小鼠表现出较差的结果。在经阴道再次接触或激发HSV-2后，接种疫苗的小鼠死亡率显著更高、疾病严重程度更高、病毒脱落更多，并且阴道分泌物中的促炎细胞因子和趋化因子水平更高。此外，小鼠在激发/再次接触后T1细胞反应受损，阴道IFN-γ CD4 T细胞的比例显著更低。小鼠中T1细胞反应受损与免疫后生殖道中IFN-γ CD4组织驻留记忆T（T）细胞群体较小一致。综上所述，这些发现描述了IL-17A在调节阴道中抗病毒IFN-γ T1细胞免疫方面的新作用。该策略可用于增强HSV-2疫苗接种后的抗病毒免疫。1型辅助性T细胞（T1）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T1反应中起重要作用。我们发现，在缺乏IL-17A的情况下，预先接触并接种疫苗的小鼠表现出较差的疾病结果，并且无法克服HSV-2的再次接触/激发。与野生型（WT）小鼠相比，IL-17A缺陷型小鼠（）免疫后生殖道中IFN-γ CD4组织驻留记忆T（T）细胞群体较小，这与激发后T1反应减弱一致。这对于开发针对HSV-2的有效疫苗具有重要意义，因为我们提出在生殖道中诱导IL-17A的策略可能促进更有效的T1细胞免疫和更好的整体保护。
