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

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Anipindi VC, Bagri P, Roth K, Dizzell SE, Nguyen PV, Shaler CR, Chu DK, Jiménez-Saiz R, Liang H, Swift S, Nazli A, Kafka JK, Bramson J, Xing Z, Jordana M, Wan Y, Snider DP, Stampfli MR, Kaushic C,


Anipindi VC, Bagri P, Roth K, Dizzell SE, Nguyen PV, Shaler CR, Chu DK, Jiménez-Saiz R, Liang H, Swift S, Nazli A, Kafka JK, Bramson J, Xing Z, Jordana M, Wan Y, Snider DP, Stampfli MR, Kaushic C, (click to view)

Anipindi VC, Bagri P, Roth K, Dizzell SE, Nguyen PV, Shaler CR, Chu DK, Jiménez-Saiz R, Liang H, Swift S, Nazli A, Kafka JK, Bramson J, Xing Z, Jordana M, Wan Y, Snider DP, Stampfli MR, Kaushic C,

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PLoS pathogens 2016 05 0512(5) e1005589 doi 10.1371/journal.ppat.1005589

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 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-1β, important factors for Th17 differentiation. Th17 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 Th17 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 Th17 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 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.

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