Regulatory T Cell–Derived Adenosine Induces Dendritic Cell Migration through the Epac-Rap1 Pathway
Regulatory T Cell–Derived Adenosine Induces Dendritic Cell Migration through the Epac-Rap1 Pathway
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DOI：
10.4049/jimmunol.1401434
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发表时间：
2015-04
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影响因子：
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通讯作者：
S. Ring;Anna Pushkarevskaya;H. Schild;H. Probst;V. Jendrossek;F. Wirsdörfer;C. Ledent;S. Robson;A. Enk;K. Mahnke
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文献类型：
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作者：
S. Ring;Anna Pushkarevskaya;H. Schild;H. Probst;V. Jendrossek;F. Wirsdörfer;C. Ledent;S. Robson;A. Enk;K. Mahnke
树突状细胞（DC）是调节性T细胞（Treg）免疫抑制的一个靶点，因为它们的相互作用导致DC中T细胞刺激能力和抑制性细胞因子的分泌降低。我们表明，DC在Treg的存在下是更移动的相比，与传统的CD 4 + T细胞的共培养物，并形成DC-Treg聚集体在2小时的培养。DC的迁移特异性地指向Treg，因为Treg而不是CD 4 + T细胞在Boyden室中吸引DC。缺乏外核苷酸酶CD 39的Treg不能吸引DC。同样地，A2 A腺苷受体拮抗剂的添加消除了DC-Treg簇的形成，表明腺苷在指导DC-Treg相互作用中的作用。对DC与Treg接触后的信号转导事件的分析显示cAMP水平增加，随后Epac 1和GTdR Rap 1活化。随后激活的Rap 1定位于DC中的皮层下肌动蛋白细胞骨架，提供了一种促进DC向Treg定向运动的手段。总的来说，这些数据表明Treg通过CD 39将ATP降解为腺苷，通过激活Epac 1-Rap 1依赖性途径吸引DC。因此，形成DC-Treg簇，并且使得DC刺激性降低。因此，这种腺苷介导的DC吸引可能是Treg调节DC诱导免疫应答的一种机制。
Dendritic cells (DC) are one target for immune suppression by regulatory T cells (Treg), because their interaction results in reduced T cell stimulatory capacity and secretion of inhibitory cytokines in DC. We show that DC in the presence of Treg are more mobile as compared with cocultures with conventional CD4+ T cells and form DC–Treg aggregates within 2 h of culture. The migration of DC was specifically directed toward Treg, as Treg, but not CD4+ T cells, attracted DC in Boyden chambers. Treg deficient for the ectonucleotidase CD39 were unable to attract DC. Likewise, addition of antagonists for A2A adenosine receptors abolished the formation of DC–Treg clusters, indicating a role for adenosine in guiding DC–Treg interactions. Analysis of the signal transduction events in DC after contact to Treg revealed increased levels of cAMP, followed by activation of Epac1 and the GTPase Rap1. Subsequently activated Rap1 localized to the subcortical actin cytoskeleton in DC, providing a means by which directed locomotion of DC toward Treg is facilitated. In aggregate, these data show that Treg degrade ATP to adenosine via CD39, attracting DC by activating Epac1-Rap1–dependent pathways. As a consequence, DC–Treg clusters are formed and DC are rendered less stimulatory. This adenosine-mediated attraction of DC may therefore act as one mechanism by which Treg regulate the induction of immune responses by DC.