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

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 (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.

IL‐17A contributes to HSV1 infection‐induced acute lung injury in a mouse model of pulmonary fibrosis

“…Our results showed that IL‐17A knockout might not influence the clearance of HSV virus (). Bagri and colleges also reported that HSV viral titres in IL‐17A ‐/‐ mice were not significantly different from that of WT mice during genital HSV infection . However, neither our results nor Bagri's work were actual measurements from the lung.…”

Parenteral vaccination protects against transcervical infection with Chlamydia trachomatis and generate tissue-resident T cells post-challenge

“…13 IL-17 has been shown to be important for establishing a Th1 response in a murine model of genital Chlamydia infection and in the Herpes simplex virus 2 animal model. 13,19,20 Whether IL-17 plays a similar role during a C.t. infection remains to be shown.…”

“…This is interesting since previous data suggested that Th17 T cells may have a role in inducing pathology. [12][13][14][15][16][17][18][19][20] As the Th17 T cell cytokine profile differed markedly from the Th17 cytokine profile in nonvaccinated/infected animals (that developed pathology), it could be speculated that only certain Th17 T cell subsets are associated with pathology, and that a Th17-inducing vaccine can prevent induction of the pathology-inducing Th17 T cells that are normally induced by the infection itself.…”

“…12 However, further studies of Th17 T cells are required to determine their role, in particular as previous studies suggested that this particular subset of T cells may induce pathology rather than protect against it. [12][13][14][15][16][17][18][19][20] Although a parenteral vaccine has proven effective against a vaginal infection with C.t. [21][22][23] or C.m., [24][25][26][27][28][29][30] in the TC C.t.…”

Origins of CD4+ circulating and tissue‐resident memory T‐cells

“…Much like circulating CD4 + memory T-cells, studies of tissue-resident lymphocytes have predominantly focused on CD8 + T RM due to the heterogeneity of CD4 + memory T-cells and the existing gaps in knowledge regarding mechanisms governing memory CD4 + T-cell formation. Nevertheless, recent studies have highlighted a prominent population of long-lived CD4 + T-cells within many nonlymphoid tissues, including the lungs, 36,[49][50][51][52][53][54][55][56][57] small intestine (SI), 12,18,[58][59][60] skin, 15,[61][62][63][64] and female reproductive tract (FRT) 18,65,66 (Fig. 2).…”