Estradiol Enhances CD4 ⁺ T-Cell Anti-Viral Immunity by Priming Vaginal DCs to Induce T _h17 Responses via an IL-1-Dependent Pathway

Abstract

Clinical and experimental studies have shown that estradiol (E2) confers protection against HIV and other sexually transmitted infections. Here, we investigated the underlying mechanism. Better protection in E2-treated mice, immunized against genital HSV-2, coincided with earlier recruitment and higher proportions of T _h1 and T _h17 effector cells in the vagina post-challenge, compared to placebo-treated controls. Vaginal APCs isolated from E2-treated mice induced 10-fold higher T _h17 and T _h1 responses, compared to APCs from progesterone-treated, placebo-treated, and estradiol-receptor knockout mice in APC-T cell co-cultures. CD11c ⁺ DCs in the vagina were the predominant APC population responsible for priming these T _h17 responses, and a potent source of IL-6 and IL-1β, important factors for T _h17 differentiation. T _h17 responses were abrogated in APC-T cell co-cultures containing IL-1β KO, but not IL-6 KO vaginal DCs, showing that IL-1β is a critical factor for T _h17 induction in the genital tract. E2 treatment in vivo directly induced high expression of IL-1β in vaginal DCs, and addition of IL-1β restored T _h17 induction by IL-1β KO APCs in co-cultures. Finally, we examined the role of IL-17 in anti-HSV-2 memory T cell responses. IL-17 KO mice were more susceptible to intravaginal HSV-2 challenge, compared to WT controls, and vaginal DCs from these mice were defective at priming efficient T _h1 responses in vitro, indicating that IL-17 is important for the generation of efficient anti-viral memory responses. We conclude that the genital mucosa has a unique microenvironment whereby E2 enhances CD4 ⁺ T cell anti-viral immunity by priming vaginal DCs to induce T _h17 responses through an IL-1-dependent pathway.

Author Summary

Female sex hormones can affect susceptibility and immune responses to infections. While a number of previous studies, including our own, have shown that progesterone and progesterone-derived hormonal contraceptives increase susceptibility and impair immune responses, estradiol protects against sexually transmitted infections. The reason why estradiol is protective remains unknown. In this study, we investigated the effect of estradiol on dendritic cells, specialized immune cells that determine what type of anti-viral cellular immune responses will be mounted following infection with a sexually transmitted virus, HSV-2. Our studies show that estradiol influences dendritic cells in the vaginal tract of mice to initiate unique anti-viral T cell immunity that results in better protection against genital HSV-2 infection. This type of T cell response is unique to the vaginal tract and not found in any other mucosal lining of the body. This is the first study to show directly that estradiol, a female sex hormone, can determine how well the immune system will combat a sexually transmitted viral infection. The information from this study will be very important in understanding what type of immunity can protect women from sexually transmitted infections and how we can use this information to develop better vaccines.