Estrogen-mediated immunomodulation involves reduced activation of effector T cells, potentiation of Treg cells, and enhanced expression of the PD-1 costimulatory pathway
Estrogen-mediated immunomodulation involves reduced activation of effector T cells, potentiation of Treg cells, and enhanced expression of the PD-1 costimulatory pathway
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DOI：
10.1002/jnr.20881
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发表时间：
2006-08-01
影响因子：
4.2
通讯作者：
Offner, Halina
中科院分区：
文献类型：
--
作者：
Polanczyk, Magdalena J.;Hopke, Corwyn;Offner, Halina
雌激素（E2）诱导的免疫调节涉及对抗原呈递细胞（APC）和CD4(+)CD25（+）调节性T细胞（Treg）的双重作用，但对效应T细胞没有直接作用。在本报告中，我们进一步研究了E2对APC和Treg功能的影响。我们发现，体内E2治疗可显著降低腹腔APC的恢复，抑制炎症细胞因子白介素(IL)-12和干扰素- γ的诱导，但增强IL-10的分泌。此外，e2条件下的骨髓源性树突状细胞（BM-DC）既能增强Treg活性，又能在Treg细胞缺失的情况下直接抑制应答T细胞。我们研究了e2诱导的BM-DC抑制活性是否可能通过最近描述的PD-1途径参与共刺激。E2和妊娠均显著提高了几种APC细胞中PD-1的表达，包括巨噬细胞、B细胞，尤其是树突状细胞（DC）。与e2诱导的FoxP-3表达增强和实验性自身免疫性脑脊髓炎保护类似，e2诱导的PD-1（+）细胞的增强也通过雌激素受体α (Esr1)介导，但不通过B细胞介导。基于抗体抑制研究，PD-1与其配体PDL-1，特别是PDL-2的相互作用，可以在成熟和未成熟的e2条件DC中介导正或负调节信号，分别取决于相对较高（10:1）或较低（1:1）的T细胞：bmp -DC。这些新发现表明e2诱导的免疫调节在一定程度上是通过增强PD-1共刺激通路介导的。(c) 2006 Wiley-Liss, Inc。
Estrogen (E2)-induced immunomodulation involves dual effects on antigen-presenting cells (APC) and CD4(+)CD25(+) regulatory T cells (Treg) but not a direct effect on effector T cells. In this report, we further investigated the effects of E2 on APC and Treg function. We found that E2 treatment in vivo strongly reduced recovery of APC from the peritoneal cavity and inhibited induction of the inflammatory cytokines interleukin (IL)-12 and interferon-gamma but enhanced secretion of IL-10. Moreover, E2-conditioned bone marrow-derived dendritic cells (BM-DC) could both enhance Treg activity and directly inhibit responder T cells in the absence of Treg cells. We examined whether this E2-induced inhibitory activity of BM-DC might involve costimulation through the recently described PD-1 pathway. Both E2 and pregnancy markedly enhanced PD-1 expression in several types of APC, including macrophages, B cells, and especially dendritic cells (DC). Similarly to E2-induced enhancement of FoxP-3 expression and experimental autoimmune encephalomyelitis protection, E2-induced enhancement of PD-1(+) cells was also mediated through estrogen receptor alpha (Esr1) in DC and macrophages but not in B cells. Based on antibody inhibition studies, PD-1 interaction with its ligands, PDL-1 and especially PDL-2, could mediate either positive or negative regulatory signaling in both mature and immature E2-conditioned DC, depending, respectively, on a relatively high (10:1) or low (1:1) ratio of T cells:BM-DC. These novel findings indicate that E2-induced immunomodulation is mediated in part through potentiation in BM-DC of the PD-1 costimulatory pathway. (c) 2006 Wiley-Liss, Inc.