Estradiol Enhances Antiviral CD4⁺Tissue-Resident Memory T Cell Responses following Mucosal Herpes Simplex Virus 2 Vaccination through an IL-17-Mediated Pathway

Abstract

Estradiol (E2) is a sex hormone which has shown to be protective against sexually transmitted infections such as herpes simplex virus 2 (HSV-2). However, few studies have examined the underlying mechanisms by which this occurs. Here, we investigated the effect of E2 on the establishment of memory T cells post-intranasal immunization with HSV-2. CD4+ T cell responses first appeared in the upper respiratory tract (URT) within 3 days post-immunization, before being detected in the female reproductive tract (FRT) at 7 days. E2 treatment resulted in greater and earlier Th17 responses, which preceded augmented Th1 responses in these sites. The CD4+ T cells persisted in the URT for up to 28 days, and E2 treatment resulted in higher frequencies of memory T cells. Intranasal immunization also led to the establishment of CD4+ tissue-resident memory T cells (TRM cells) in the FRT, and E2 treatment resulted in increased Th1 and Th17 TRM cells. When the migration of circulating T cells into the FRT was blocked by FTY720, immunized E2-treated mice remained completely protected against subsequent genital HSV-2 challenge compared to non-E2 controls, confirming that TRM cells alone are adequate for protection in these mice. Finally, the enhanced vaginal Th1 TRM cells present in E2-treated mice were found to be modulated through an IL-17-mediated pathway, as E2-treated IL-17A deficient mice had impaired establishment of Th1 TRM cells. This study describes a novel role for E2 in enhancing CD4+ memory T cells and provides insight on potential strategies for generating optimal immunity during vaccination. IMPORTANCE Herpes simplex virus 2 (HSV-2) is a highly prevalent sexually transmitted infection for which there is currently no vaccine available. Interestingly, the female sex hormone estradiol has been shown to be protective against HSV-2. However, the underlying mechanisms by which this occurs remains relatively unknown. Our study demonstrates that under the influence of estradiol treatment, intranasal immunization with an attenuated strain of HSV-2 leads to enhanced establishment of anti-viral memory T cell responses in the upper respiratory tract and female reproductive tract. In these sites, estradiol treatment leads to greater Th17 memory cells, which precede enhanced Th1 memory responses. Consequently, the T cell responses mounted by tissue-resident memory cells in the female reproductive tract of estradiol-treated mice are sufficient to protect mice against vaginal HSV-2 challenge. This study offers important insights regarding the regulation of mucosal immunity by hormones and on potential strategies for generating optimal immunity during vaccination.

The Role of IL-17 During Infections in the Female Reproductive Tract

“…Our work over the past few years has provided significant insight regarding how IL-17 modulates critical anti-viral T cell responses in the FRT. While it is well established that anti-viral protection against HSV-2 in the mouse model of infection is largely mediated by Th1 responses ( 115 – 117 ), our findings are the first to show that Th17 responses are also important in the anti-viral immune response to HSV-2 infection ( 118 – 120 ). We directly examined the role of IL-17 in anti-viral protection against HSV-2 and found that compared to WT controls, IL-17A-/- mice immunized intravaginally or intranasally were more susceptible to HSV-2 challenge ( 119 ).…”

“…For the past decade we have investigated the influence of E2 on immune responses in the FRT and found that E2 increases protection against HSV-2 infection, although the underlying immunological mechanisms remained unclear. Recently, we showed that better protection in E2-treated mice coincided with earlier recruitment and higher proportions of Th1 and Th17 cells in the FRT following either HSV-2 immunization (intravaginally or intranasally) ( 120 ) and/or challenge ( 118 ). This included greater establishment of tissue-resident memory CD4+ T cells in the FRT, which play a critical role against re-exposure to pathogens ( 120 ).…”

Effect of Female Sex Hormones on the Immune Response against Chlamydia abortus and on Protection Conferred by an Inactivated Experimental Vaccine in a Mouse Model

“…For example, oestradiol has been described to enhance the neutralising antibody titre in mouse models of infection with genital herpesvirus type II (HSV-2) infection ( [30,31]) and H1N1 [17]. Furthermore, in another vaccination model of HSV-2, oestradiol has been shown to increase dendritic cell activity by producing inflammatory cytokines such as IL-1beta [32] and more recently, this hormone has also been shown to increase the number of CD4+ memory T cells in tissue through a IL-17 mediated pathway [33].…”

Tissue-resident immunity in the female and male reproductive tract

“…An alternative option to boost the formation of T RM cells involves hormonal treatments. Hereby, the co-administration of estradiol after initial intranasal immunization with HSV-2 led to increased Th1 and Th17 T RM cell frequencies with protective capabilities upon genital HSV-2 re-challenge [ 28 ].…”