Dendritic cell immunoreceptor: A novel receptor for intravenous immunoglobulin mediates induction of regulatory T cells
Dendritic cell immunoreceptor: A novel receptor for intravenous immunoglobulin mediates induction of regulatory T cells
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DOI：
10.1016/j.jaci.2013.09.029
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发表时间：
2014-03-01
影响因子：
14.2
通讯作者：
Mazer, Bruce D.
中科院分区：
文献类型：
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作者：
Massoud, Amir H.;Yona, Madelaine;Mazer, Bruce D.
背景：静脉注射免疫球蛋白（IVIg）是一种多克隆IgG制剂，具有有效的免疫调节特性。我们的实验室证明，在过敏性气道疾病模型中，IVIg通过产生耐受性树突状细胞（dc）显著增加叉头盒蛋白3阳性调节性T （Treg）细胞的数量。目的：我们试图研究dc上介导这些事件的潜在受体。方法：将C57BL/6小鼠分别通过腹腔或过继性转移卵清蛋白（OVA）致敏，然后用鼻内OVA致敏。IVIg分为富含唾液酸的IVIg （SA-IVIg）和缺乏唾液酸的IVIg （non-SA-IVIg）。用荧光显微镜和流式细胞术检测树突状细胞免疫受体（DCIR）在CHO细胞和dc细胞上的表达。结果：与IVIg相比，SA-IVIg（非SA-IVIg）对ova致敏和ova挑战小鼠可诱导Treg细胞，并减轻气道高反应性（AHR）和炎症。用SA-IVIg或IVIg培养的骨髓源树突状细胞过继转移到小鼠体内，在卵细胞攻击前诱导Treg细胞并抑制AHR。来自Fc γ受体敲除小鼠的经IVIg处理的骨髓来源的树突状细胞抑制AHR，表明IVIg的作用不是由Fc γ受体介导的事件引起的。荧光标记IVIg或SA-IVIg结合dc，并特异性定位于c型凝集素DCIR。IVIg结合DCIR诱导Src同源结构域2-含蛋白酪氨酸磷酸酶（SHP） 2和Src同源结构域2-含肌醇磷酸酶1 （SHIP-1）磷酸化，IVIg内化到DCs中。通过小干扰RNA抑制IVIg与DCIR的结合完全阻断了Treg细胞的诱导。通过聚集蛋白抑制剂抑制SHP-2或消除IgG内化使IVIg无效。结论：IVIg可通过SA-IgG与DCIR的相互作用减轻变应性气道疾病。DCIR是一种新的IVIg受体，在耐受性反应中介导先天免疫和适应性免疫的相互作用。
Background: Intravenous immunoglobulin (IVIg) is a polyclonal IgG preparation with potent immunomodulating properties. Our laboratory demonstrated that IVIg significantly increases numbers of forkhead box protein 3-positive regulatory T (Treg) cells through generation of tolerogenic dendritic cells (DCs) in an allergic airways disease model.Objective: We sought to investigate potential receptors on DCs mediating these events.Methods: C57BL/6 mice were either sensitized to ovalbumin (OVA) intraperitoneally or through adoptive transfer of OVA-primed DCs and then challenged with intranasal OVA. IVIg was fractionated into sialic acid-enriched IVIg (SA-IVIg) and sialic acid-depleted IVIg (non-SA-IVIg). Dendritic cell immunoreceptor (DCIR) constructs in CHO cells or on DCs were examined by using fluorescent microscopy and flow cytometry.Results: Administration of SA-IVIg, but not non-SA-IVIg, to OVA-sensitized and OVA-challenged mice induced Treg cells and attenuated airway hyperresponsiveness (AHR) and inflammation comparably with IVIg. Bone marrow-derived dendritic cells cultured with SA-IVIg or IVIg adoptively transferred to mice before OVA challenge induced Treg cells and inhibited AHR. IVIg-treated bone marrow-derived dendritic cells from Fc gamma receptor knockout mice inhibited AHR, suggesting IVIg's action was not caused by Fc gamma receptor-mediated events. Fluorescently labeled IVIg or SA-IVIg bound DCs and colocalized specifically to the C-type lectin DCIR. IVIg binding to DCIR induced phosphorylation of Src homology domain 2-containing protein tyrosine phosphatase (SHP) 2 and Src homology domain 2-containing inositol phosphatase 1 (SHIP-1) and internalization of IVIg into DCs. Inhibition of IVIg binding to DCIR by small interfering RNA completely blocked induction of Treg cells. Inhibition of SHP-2 or abrogation of IgG internalization through clatherin inhibitors rendered IVIg ineffective.Conclusions: IVIg alleviates allergic airways disease through interaction of SA-IgG with DCIR. DCIR is a novel receptor for IVIg, mediating interaction of innate and adaptive immunity in tolerogenic responses.