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

Estradiol (E2) is a sex hormone which has been 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 postimmunization 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 at 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 interleukin 17 (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 antiviral 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.

A mixture of five endocrine-disrupting chemicals modulates concentrations of bisphenol A and estradiol in mice.

Most people in developed countries are exposed to multiple endocrine-disrupting synthetic chemicals. We previously showed that a single dose of triclosan, tetrabromobisphenol A (TBBPA), butyl paraben, propyl paraben, or di(2-ethylhexyl) phthalate elevated concentrations of bisphenol A (BPA) in mice. Here we investigated whether concurrent exposure to lower doses of these five chemicals could modulate concentrations of bisphenol A (BPA) or the natural estrogen, 17ß-estradiol (E2). CF1 mice were injected subcutaneously with 0.1 or 0.5 mg of one chemical, or a 0.5 mg mixture containing 0.1 mg of each of all five chemicals, then given dietary 50 µg kg-114C-BPA. The mixture elevated 14C-BPA concentrations in the lungs, muscle, uterus, ovaries, kidney, and blood serum of female mice. When administered alone, triclosan and TBBPA elevated 14C-BPA concentrations in the uterus, ovaries, and blood serum. In another experiment, CF1 mice were injected subcutaneously with the 0.5 mg mixture containing 0.1 mg of all five chemicals, then E2 was measured in urine 2-12 h later. The mixture elevated E2 at 8 h after injection in female mice. No treatments significantly altered concentrations of 14C-BPA or E2 in male mice. These data show that these endocrine-disrupting chemicals interact in vivo, magnifying one another's effects, consistent with inhibition of enzymes that are critical for estrogen metabolism. These findings highlight the importance of considering exposure to multiple chemicals when assessing health outcomes and determining regulatory exposure limits.

Butyl paraben and propyl paraben modulate bisphenol A and estradiol concentrations in female and male mice.

People are routinely exposed to the antimicrobial preservatives butyl paraben (BP) and propyl paraben (PP), as well as the monomer of polycarbonate plastics, bisphenol A (BPA). These chemicals are reliably detected in human urine and potentially interact. We investigated whether BP or PP exposure can modulate the concentrations of 14C-BPA and 17ß-estradiol (E2). Female and male CF1 mice were each given a subcutaneous injection of oil containing 0 (vehicle), 1, 3, or 9mg BP or PP, then given a dietary supplement containing 50µg/kg 14C-BPA. Radioactivity was measured in tissues through liquid scintillation counting. Significantly elevated 14C-BPA concentrations were observed following BP treatment in blood serum of both sexes, as well as the lungs, uterus, and ovaries of females and the testes and epididymides of males. Treatment with PP significantly elevated 14C-BPA concentrations in the uterus only. In another experiment, female and male CF1 mice were each injected with vehicle, 3mg BP, or 3mg PP, and E2 was measured in urine 2-12h later. Whereas PP did not affect E2, BP significantly elevated E2 6-10h after injection in females and 8h after injection in males. These data indicate that BP and PP can alter the pharmacokinetics of BPA in vivo, and that BP can modulate E2 concentrations. These results are consistent with evidence that parabens inhibit enzymes that are critical for BPA and E2 metabolism, and demonstrate the importance of considering concurrent exposure to multiple chemicals when determining regulatory exposure limits.