Correction: Estradiol Enhances CD4+ T-Cell Anti-Viral Immunity by Priming Vaginal DCs to Induce Th17 Responses via an IL-1-Dependent Pathway.

[This corrects the article DOI: 10.1371/journal.ppat.1005589.].

Estradiol Enhances CD4+ T-Cell Anti-Viral Immunity by Priming Vaginal DCs to Induce Th17 Responses via an IL-1-Dependent Pathway.

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 Th1 and Th17 effector cells in the vagina post-challenge, compared to placebo-treated controls. Vaginal APCs isolated from E2-treated mice induced 10-fold higher Th17 and Th1 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 Th17 responses, and a potent source of IL-6 and IL-1ß, important factors for Th17 differentiation. Th17 responses were abrogated in APC-T cell co-cultures containing IL-1ß KO, but not IL-6 KO vaginal DCs, showing that IL-1ß is a critical factor for Th17 induction in the genital tract. E2 treatment in vivo directly induced high expression of IL-1ß in vaginal DCs, and addition of IL-1ß restored Th17 induction by IL-1ß 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 Th1 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 Th17 responses through an IL-1-dependent pathway.

Innate and adaptive immune responses in male and female reproductive tracts in homeostasis and following HIV infection.

The male and female reproductive tracts are complex microenvironments that have diverse functional demands. The immune system in the reproductive tract has the demanding task of providing a protective environment for a fetal allograft while simultaneously conferring protection against potential pathogens. As such, it has evolved a unique set of adaptations, primarily under the influence of sex hormones, which make it distinct from other mucosal sites. Here, we discuss the various components of the immune system that are present in both the male and female reproductive tracts, including innate soluble factors and cells and humoral and cell-mediated adaptive immunity under homeostatic conditions. We review the evidence showing unique phenotypic and functional characteristics of immune cells and responses in the male and female reproductive tracts that exhibit compartmentalization from systemic immunity and discuss how these features are influenced by sex hormones. We also examine the interactions among the reproductive tract, sex hormones and immune responses following HIV-1 infection. An improved understanding of the unique characteristics of the male and female reproductive tracts will provide insights into improving clinical treatments of the immunological causes of infertility and the design of prophylactic interventions for the prevention of sexually transmitted infections.

HSV-2 vaccine: current state and insights into development of a vaccine that targets genital mucosal protection.

HSV-2 is one of the most prevalent sexually transmitted infections that result in significant morbidity and financial burden on health systems around the world. Recurrent and asymptomatic re-activation accompanied by viral shedding is common among sero-positive individuals, leading to relatively high efficiency of transmission. Prophylactic HSV-2 vaccines are the best and cheapest option to address the problems associated with HSV-2 infections globally. However, despite persistent efforts, the search for an efficacious vaccine for HSV-2 remains elusive. In this review, the current state of HSV-2 vaccines and the outcome of past human trials are examined. Furthermore, we discuss the evidence and strategies from experimental mouse models that have been successful in inducing protective immunity in the genital tract against HSV-2, following immunization. Future vaccination strategies that focus on induction of robust mucosal immunity in the genital tract may hold the key for a successful vaccine against HSV-2.

Increased prevalence of sexually transmitted viral infections in women: the role of female sex hormones in regulating susceptibility and immune responses.

Sexually transmitted infections (STIs) caused by viruses, including HSV-2, HIV-1, HPV, are among the most prevalent infectious diseases worldwide and a major cause of morbidity and mortality. Despite decades of effort, the attempts to develop efficacious vaccines against viral STIs have failed repeatedly, with the exception of the recent HPV vaccine. Given the higher prevalence rates of STIs in women, it is becoming clear that a better understanding of gender-specific differences in STIs may be critical for the development of preventative strategies for these diseases. In order to gain this insight, it is important to examine the distinct microenvironment of the female reproductive tract, the site of primary infection, since it can significantly influence the outcome of infection. An important biological factor in the female reproductive tract is the presence of female sex hormones, estrogen and progesterone, which are produced endogenously primarily by the ovaries and commonly provided exogenously via the use of hormonal contraceptives. Here we review our current knowledge of the role played by the female sex hormones in regulating susceptibility and immune responses to viral sexually transmitted infections and whether this could contribute to higher prevalence of STIs in women. Manipulating the microenvironment of the female genital tract with sex hormones may contribute to the development of improved immunization strategies against sexually transmitted infections.

Positive and negative regulatory mechanisms in high-affinity IgE receptor-mediated mast cell activation.

Mast cells are important effector cells in allergic inflammatory reactions. The aggregation of the high-affinity IgE receptor (FcepsilonRI) on the surface of mast cells initiates a complex cascade of signaling events that ultimately leads to the release of various mediators involved in allergic inflammation and anaphylactic reactions. The release of these mediators is tightly controlled by signaling pathways that are propagated through the cell by specific phosphorylation and dephosphorylation events. These events are controlled by protein kinases and protein phosphatases which either positively or negatively regulate the propagation of the signal through the cell. This review summarizes the role of both positive and negative regulators of FcepsilonRI-induced mast cell activation.

TRAF6 specifically contributes to FcepsilonRI-mediated cytokine production but not mast cell degranulation.

TRAF6 (tumor necrosis factor-associated factor 6) is an essential adaptor downstream from the tumor necrosis factor (TNF) receptor and Toll-like receptor superfamily members. This molecule is critical for dendritic cell maturation and T cell homeostasis. Here we show that TRAF6 is important in high affinity IgE receptor, FcepsilonRI-mediated mast cell activation. In contrast to dendritic cells and T cells, TRAF6-deficient mast cells matured normally and showed normal IgE-dependent degranulation. Importantly, TRAF6-deficient mast cells showed impaired production of cytokine interleukin-6, CCL-9, interleukin-13, and TNF following FcepsilonRI aggregation. Chromatin immunoprecipitation assay showed decreased NF-kappaB p65 binding to CCL-9 and TNF promoters in TRAF6-deficient mast cells. Antigen and IgE-induced IkappaB phosphorylation and NF-kappaB p65 translocation to the nucleus were diminished in TRAF6-deficient mast cells. NF-kappaB luciferase activity in response to antigen and IgE stimulation was severely impaired in TRAF6-deficient mast cells. In addition, antigen and IgE-induced phosphorylation of mitogen-activated protein kinase p38 and JNK, but not ERK1/2, was significantly reduced in TRAF6-deficient mast cells. These results identified TRAF6 as an important signal transducer in FcepsilonRI-mediated signaling in mast cells. Our findings implicate TRAF6 as a new adaptor/regulator molecule for allergen-mediated inflammation in allergy.