PDCD5 negatively regulates autoimmunity by upregulating FOXP3+ regulatory T cells and suppressing Th17 and Th1 responses
PDCD5 negatively regulates autoimmunity by upregulating FOXP3+ regulatory T cells and suppressing Th17 and Th1 responses
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PDCD5 通过上调 FOXP3( ) 调节性 T 细胞并抑制 Th17 和 Th1 反应来负向调节自身免疫
DOI：
10.1016/j.jaut.2013.08.002
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发表时间：
2013-12-01
影响因子：
12.8
通讯作者：
Chen, Yingyu
中科院分区：
文献类型：
--
作者：
Xiao, Juan;Liu, Chen;Chen, Yingyu
叉头框蛋白P3（FOXP3）蛋白表达的维持对于调节性T（Treg）细胞的分化和成熟至关重要，Treg细胞在免疫稳态和免疫耐受中发挥着重要作用。我们在此证明，程序性细胞死亡蛋白5（PDCD5）与FOXP3相互作用，与Tip60协同增加FOXP3的乙酰化，并增强FOXP3的抑制功能。在PDCD5转基因（PDCD5tg）小鼠中，PDCD5的过表达提高了FOXP3蛋白水平以及CD4⁺CD25⁺FOXP3⁺细胞的百分比。来自PDCD5tg小鼠的初始CD4⁺ T细胞对转化生长因子-β（TGF-β）诱导的Treg极化和扩增更为敏感。这些诱导产生的Tregs在体外保持正常的抑制功能。与野生型小鼠相比，PDCD5tg小鼠实验性自身免疫性脑脊髓炎（EAE）的严重程度显著降低。PDCD5的有益作用可能源于Treg细胞频率的增加，同时主要致病性辅助性T细胞17（Th17）/辅助性T细胞1（Th1）应答减少。PDCD5增强的激活诱导细胞死亡也与这一过程相关。这是首次有报道揭示T细胞中的PDCD5活性通过调节Tregs来抑制自身免疫。本研究表明，PDCD5是免疫功能的守护者，且PDCD5 - FOXP3 - Treg轴可能是自身免疫疾病的一个治疗靶点。（C）2013爱思唯尔有限公司。保留所有权利。
Maintenance of FOXP3 protein expression is crucial for differentiation and maturation of regulatory T (Treg) cells, which play important roles in immune homeostasis and immune tolerance. We demonstrate here that PDCD5 interacts with FOXP3, increases acetylation of FOXP3 in synergy with Tip60 and enhances the repressive function of FOXP3. In PDCD5 transgenic (PDCD5tg) mice, overexpression of PDCD5 enhanced the level of FOXP3 protein and percentage of CD4(+)CD25(+)FOXP3(+) cells. Naive CD4(+) T cells from PDCD5tg mice were more sensitive to TGF-beta-induced Treg polarization and expansion. These induced Tregs retained normal suppressive function in vitro. Severity of experimentally-induced autoimmune encephalomyelitis (EAE) in PDCD5tg mice was significantly reduced relative to that of wild-type mice. The beneficial effect of PDCD5 likely resulted from increases of Treg cell frequency, accompanied by a reduction of the predominant pathogenic Th17/Th1 response. Activation-induced cell death enhanced by PDCD5 was also linked to this process. This is the first report revealing that PDCD5 activity in T cells suppresses autoimmunity by modulating Tregs. This study suggests that PDCD5 serves as a guardian of immunological functions and that the PDCD5-FOXP3-Treg axis may be a therapeutic target for autoimmunity. (C) 2013 Elsevier Ltd. All rights reserved.