PD-1 modulates regulatory T-cell homeostasis during low-dose interleukin-2 therapy
PD-1 modulates regulatory T-cell homeostasis during low-dose interleukin-2 therapy
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DOI：
10.1182/blood-2016-09-741629
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发表时间：
2017-04-13
期刊：
影响因子：
20.3
通讯作者：
Matsuoka, Ken-ichi
中科院分区：
文献类型：
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作者：
Asano, Takeru;Meguri, Yusuke;Matsuoka, Ken-ichi
CD 4（+）Foxp 3（+）调节性T细胞（Treg）在造血干细胞移植后免疫耐受的维持中起着重要作用。我们以前报道过，低剂量白细胞介素-2（IL-2）治疗增加了循环T细胞，改善了慢性移植物抗宿主病（cGVHD）的临床症状;然而，在IL-2治疗期间调节Treg稳态的机制尚未得到很好的研究。为了阐明这些调节机制，我们研究了抑制性辅助受体在IL-2治疗小鼠模型和cGVHD患者中对TcR的作用。小鼠研究表明，低剂量IL-2选择性地增加了TcM，同时增强了程序性细胞死亡1（PD-1）的表达，特别是在CD 44（+）CD 62 L（+）中枢记忆TcM上，而其他抑制分子（包括CTLA-4、LAG-3和TIM-3）的表达保持稳定。PD-1缺陷型TcB在IL-2启动后不久显示快速的Stat 5磷酸化和增殖，但此后TcB变得具有较高的Fas和较低的Bcl-2表达的促凋亡。结果，IL-2对Treg的积极影响被完全消除，尽管持续给予IL-2，Treg水平仍恢复至基线。我们还检查了接受低剂量IL-2治疗的cGVHD患者的循环TcR，发现IL-2诱导的Treg增殖后，中枢记忆TcR上的PD-1表达迅速增加。值得注意的是，GVHD的临床改善与Treg上PD-1水平的增加相关，表明PD-1途径支持Treg介导的耐受性。这些研究表明，PD-1通过在IL-2治疗期间调节增殖和凋亡，是T细胞增殖的关键稳态调节剂。我们的研究结果将促进调节Treg稳态以促进免疫耐受的治疗策略的发展。
CD4(+) Foxp3(+) regulatory T cells (Tregs) play a central role in the maintenance of immune tolerance after hematopoietic stem cell transplantation. We previously reported that low-dose interleukin-2 (IL-2) therapy increased circulating Tregs and improved clinical symptoms of chronic graft-versus-host-disease (cGVHD); however, the mechanisms that regulate Treg homeostasis during IL-2 therapy have not been well studied. To elucidate these regulatory mechanisms, we examined the role of inhibitory coreceptors on Tregs during IL-2 therapy in a murine model and in patients with cGVHD. Murine studies demonstrated that low-dose IL-2 selectively increased Tregs and simultaneously enhanced the expression of programmed cell death 1 (PD-1), especially on CD44(+) CD62L(+) central-memory Tregs, whereas expression of other inhibitory molecules, including CTLA-4, LAG-3, and TIM-3 remained stable. PD-1-deficient Tregs showed rapid Stat5 phosphorylation and proliferation soon after IL-2 initiation, but thereafter Tregs became proapoptotic with higher Fas and lower Bcl-2 expression. As a result, the positive impact of IL-2 on Tregs was completely abolished, and Treg levels returned to baseline despite continued IL-2 administration. We also examined circulating Tregs from patients with cGVHD who were receiving low-dose IL-2 and found that IL-2-induced Treg proliferation was promptly followed by increased PD-1 expression on central-memory Tregs. Notably, clinical improvement of GVHD was associated with increased levels of PD-1 on Tregs, suggesting that the PD-1 pathway supports Treg-mediated tolerance. These studies indicate that PD-1 is a critical homeostatic regulator for Tregs by modulating proliferation and apoptosis during IL-2 therapy. Our findings will facilitate the development of therapeutic strategies that modulate Treg homeostasis to promote immune tolerance.