Estradiol Enhances CD4+ T-Cell Anti-Viral Immunity by Priming Vaginal DCs to Induce Th17 Responses via an IL-1-Dependent Pathway
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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DOI：
10.1371/journal.ppat.1005589
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发表时间：
2016-05-01
期刊：
影响因子：
6.7
通讯作者：
Kaushic, Charu
中科院分区：
文献类型：
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作者：
Anipindi, Varun C.;Bagri, Puja;Kaushic, Charu
临床和实验研究表明，雌二醇（E2）可保护人体免受艾滋病毒和其他性传播感染。在这里，我们研究了潜在的机制。与安慰剂治疗的对照组相比，E2治疗的小鼠对生殖器HSV-2免疫的保护作用更好，与更早的募集和更高比例的Th-1和T（h）17效应细胞在阴道中相一致。在APC-T细胞共培养物中，从E2处理的小鼠中分离的阴道APC诱导的T（h）17和T（h）1应答比从炔雌醇处理的、安慰剂处理的和雌二醇受体敲除小鼠中分离的APC高10倍。阴道中的CD 11 c（+）DCs是负责引发这些T（h）17应答的主要APC群体，并且是IL-6和IL-1 β的有效来源，IL-6和IL-1 β是T（h）17分化的重要因子。在含有IL-1 β KO的APC-T细胞共培养物中，T（h）17反应被消除，但在含有IL-6 KO阴道DC的APC-T细胞共培养物中，T（h）17反应未被消除，这表明IL-1 β是生殖道中T（h）17诱导的关键因素。体内E2处理直接诱导阴道DC中IL-1 β的高表达，并且加入IL-1 β恢复了共培养物中IL-1 β KO APC对T（h）17的诱导。最后，我们研究了IL-17在抗HSV-2记忆T细胞应答中的作用。与WT对照相比，IL-17 KO小鼠对阴道内HSV-2攻击更敏感，并且来自这些小鼠的阴道DC在体外引发有效T（h）1应答时有缺陷，表明IL-17对于产生有效的抗病毒记忆应答很重要。我们的结论是，生殖器粘膜有一个独特的微环境，其中E2增强CD 4（+）T细胞的抗病毒免疫，通过启动阴道DCs诱导T（h）17反应，通过IL-1依赖性途径。
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 Th-1 and T(h)17 effector cells in the vagina post-challenge, compared to placebo-treated controls. Vaginal APCs isolated from E2-treated mice induced 10-fold higher T(h)17 and T(h)1 responses, compared to APCs from progesterone-treated, placebo-treated, and estradiol-receptor knockout mice in APC-T cell cocultures. CD11c(+) DCs in the vagina were the predominant APC population responsible for priming these T(h)17 responses, and a potent source of IL-6 and IL-1 beta, important factors for T(h)17 differentiation. T(h)17 responses were abrogated in APC-T cell co-cultures containing IL-1 beta KO, but not IL-6 KO vaginal DCs, showing that IL-1 beta is a critical factor for T(h)17 induction in the genital tract. E2 treatment in vivo directly induced high expression of IL-1 beta in vaginal DCs, and addition of IL-1 beta restored T(h)17 induction by IL-1 beta 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(h)1 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(h)17 responses through an IL-1-dependent pathway.