T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance.
T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance.
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DOI：
10.1038/nature07210
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发表时间：
2008-09-11
期刊：
影响因子：
64.8
通讯作者：
O'Shea, John J.
中科院分区：
文献类型：
--
作者：
Pesu, Marko;Watford, Wendy T.;Wei, Lai;Xu, Lili;Fuss, Ivan;Strober, Warren;Andersson, John;Shevach, Ethan M.;Quezado, Martha;Bouladoux, Nicolas;Roebroek, Anton;Belkaid, Yasmine;Creemers, John;O'Shea, John J.
蛋白原转换酶(PC)是一类能在碱性氨基酸作用下裂解目标蛋白，产生成熟的、具有生物活性的多肽的蛋白转换酶家族。据报道，这个家族的创始成员Furin有许多潜在的底物。然而，毛皮的胚系缺失是胚胎致死的，因此对毛皮的细胞类型特异性功能仍然知之甚少。虽然Furin是T细胞表达的主要PC家族成员之一，由T细胞激活诱导，是Stat家族转录因子的直接靶标，但Furin在T细胞中的功能还不清楚。在这里，我们表明，T细胞中的Furin的条件缺失会导致外周耐受性的丧失，其特征是激活的T细胞过度产生Th1和Th2型细胞因子，循环自身抗体和炎症性肠病的发生。据报道，PC参与了几种关键的免疫调节细胞因子的加工，我们发现呋喃西林缺乏的T细胞损害了抗炎细胞因子转化生长因子β-1的产生。与转化生长因子β-1缺乏的T调节细胞(Treg)一样，在体内的T细胞转移性结肠炎模型中，缺乏Furin的Treg细胞的保护作用较弱。此外，还发现缺乏呋喃的效应细胞对野生型Tregs的抑制活性具有抵抗力。我们的结果表明，在维持外周耐受性方面，呋喃西林是不可或缺的，这至少部分是由于它在调节转化生长因子β-1的产生和控制生物可用转化生长因子β-1水平方面具有非多余的基本功能。这些发现揭示了Furin作为一种T细胞激活基因的特殊功能，该基因调节一种重要的免疫抑制细胞因子。然而，这一结果也可能具有更广泛的影响，因为以呋喃为靶点已成为治疗恶性和传染性疾病的一种策略。目前的工作表明，抑制Furin可能会激活免疫反应，但可能会导致外周耐受性的崩溃。
Proprotein convertases (PC) are a family of proteases that cleave target proproteins at basic aminoacids, generating mature, biologically active polypeptides. Furin, the founding member of this family, is reported to have a number of potential substrates. However, germline deletion of fur is embryonically lethal, and therefore the cell-type specific functions of furin remain poorly understood. Although furin is one of the predominant PC family members expressed by T cells, is induced by T cell activation and is a direct target of Stat family transcription factors, the function of furin in T cells is also not clear. Herein, we show that conditional deletion of furin in T cells results in loss of peripheral tolerance characterized by activated T cells that overproduce both Th1 and Th2 type cytokines, circulating autoantibodies and development of inflammatory bowel disease. PCs are reportedly involved in the processing of several key immunoregulatory cytokines and we found that furin-deficient T cells have impaired production of the anti-inflammatory cytokine TGFβ-1. Like TGFβ-1-deficient T regulatory (Treg) cells, furin-deficient Treg cells, are less protective in a T cell transfer colitis model in vivo. Furthermore, furin-deficient effector cells were found to be resistant to suppressive activity of wild-type Tregs. Our results indicate that furin is indispensable in maintaining peripheral tolerance, which is due, at least in part, to its nonredundant, essential function in regulating TGFβ-1 production and controlling the levels of bioavailable TGFβ-1. These findings shed light on the specific function of furin as a T cell activation gene that modulates an important immunosuppressive cytokine. However, the results may also have broader implications, as targeting furin has emerged as a strategy in malignant and infectious disease. The current work suggests that inhibiting furin might activate immune responses, but may result in a breakdown in peripheral tolerance.
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