Unexpected Regulatory Role of CCR9 in Regulatory T Cell Development.
Unexpected Regulatory Role of CCR9 in Regulatory T Cell Development.
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DOI：
10.1371/journal.pone.0134100
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Cong Y
中科院分区：
文献类型：
--
作者：
Evans-Marin HL;Cao AT;Yao S;Chen F;He C;Liu H;Wu W;Gonzalez MG;Dann SM;Cong Y
对微生物群反应的T细胞调节炎症性肠病（IBD）的发病机制。由于通过高度特异性趋化因子-趋化因子受体之间的相互作用来调节T细胞向肠的运输，因此已经做出努力来开发基于阻断这些关键过程的精氨酸特异性免疫抑制。CCR 9是一种由淋巴细胞和树突状细胞表达的肠道营养型趋化因子受体，通过介导T细胞向炎症部位的募集而参与IBD的调节。然而，CCR 9在IBD背景下诱导和维持炎症的作用知之甚少。在这项研究中，我们证明了效应T细胞和TcR中的CCR 9缺陷不会影响微生物群抗原特异性T细胞介导模型中结肠炎的发展。然而，与效应T细胞相比，Treg细胞表达更高水平的CCR 9。有趣的是，CCR 9抑制Treg细胞发育，因为CCR 9-/-小鼠表现出高水平的Foxp 3 + T细胞，并且CCR 9通过其配体CCL 25的连接在体外抑制Treg细胞分化。总的来说，我们的数据表明，除了作为肠道归巢分子，CCR 9信号传导通过抑制Treg细胞发育来塑造免疫应答。
T cells reactive to microbiota regulate the pathogenesis of inflammatory bowel disease (IBD). As T cell trafficking to intestines is regulated through interactions between highly specific chemokine-chemokine receptors, efforts have been made to develop intestine-specific immunosuppression based on blocking these key processes. CCR9, a gut-trophic chemokine receptor expressed by lymphocytes and dendritic cells, has been implicated in the regulation of IBD through mediating recruitment of T cells to inflamed sites. However, the role of CCR9 in inducing and sustaining inflammation in the context of IBD is poorly understood. In this study, we demonstrate that CCR9 deficiency in effector T cells and Tregs does not affect the development of colitis in a microbiota antigen-specific, T cell-mediated model. However, Treg cells express higher levels of CCR9 compared to those in effector T cells. Interestingly, CCR9 inhibits Treg cell development, in that CCR9-/- mice demonstrate a high level of Foxp3+ Tregs, and ligation of CCR9 by its ligand CCL25 inhibits Treg cell differentiation in vitro. Collectively, our data indicate that in addition to acting as a gut-homing molecule, CCR9 signaling shapes immune responses by inhibiting Treg cell development.