CCR8+FOXp3+ Treg cells as master drivers of immune regulation
CCR8+FOXp3+ Treg cells as master drivers of immune regulation
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DOI：
10.1073/pnas.1621280114
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发表时间：
2017-06-06
影响因子：
11.1
通讯作者：
Karin, Nathan
中科院分区：
文献类型：
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作者：
Barsheshet, Yiftah;Wildbaum, Gizi;Karin, Nathan
目前的研究确定CCR8(+)调节性T细胞(T-reg细胞)是免疫抑制的驱动因素。我们发现，在人类外周血细胞中，超过30%的T-reg在CCL1存在的情况下激活后上调CCR8。这种相互作用诱导依赖STAT3的Foxp3、CD39、IL-10和颗粒酶B的上调，从而增强这些细胞的抑制活性。在四种人类CCR8配体中，CCL1在增强T-reg细胞方面是唯一的。使用多发性硬化症的实验模型[实验性自身免疫性脑脊髓炎(EAE)]和稳定版本的小鼠CCL1(CCL1-Ig)，这些观察的相关性得到了扩展。首先，我们确定了一种自我喂养机制，通过这种机制，T-reg细胞在自身免疫部位产生的CCL1上调了这些细胞上自己的受体CCR8的表达。在EAE期间给予CCL1-Ig可促进这些CCR8(+)调节细胞的体内增殖，同时诱导CD39、颗粒酶B和IL-10的表达，从而有效地抑制正在进行的EAE。通过对CCR8-/-小鼠的过继转移研究，进一步剖析了CCL1-CCR8轴在T-reg细胞中的关键作用。总之，我们展示了CCR8(+)T-reg细胞在抑制免疫中的关键作用，并强调了这一发现的潜在临床意义。
The current study identifies CCR8(+) regulatory T cells (T-reg cells) as drivers of immunosuppression. We show that in human peripheral blood cells, more than 30% of T-reg up-regulate CCR8 following activation in the presence of CCL1. This interaction induces STAT3-dependent up-regulation of FOXp3, CD39, IL-10, and granzyme B, resulting in enhanced suppressive activity of these cells. Of the four human CCR8 ligands, CCL1 is unique in potentiating T-reg cells. The relevance of these observations has been extended using an experimental model of multiple sclerosis [experimental autoimmune encephalomyelitis, (EAE)] and a stabilized version of mouse CCL1 (CCL1-Ig). First, we identified a self-feeding mechanism by which CCL1 produced by T-reg cells at an autoimmune site up-regulates the expression of its own receptor, CCR8, on these cells. Administration of CCL1-Ig during EAE enhanced the in vivo proliferation of these CCR8(+) regulatory cells while inducing the expression of CD39, granzyme B, and IL-10, resulting in the efficacious suppression of ongoing EAE. The critical role of the CCL1-CCR8 axis in T-reg cells was further dissected through adoptive transfer studies using CCR8-/- mice. Collectively, we demonstrate the pivotal role of CCR8(+) T-reg cells in restraining immunity and highlight the potential clinical implications of this discovery.