Enhanced formation and survival of CD4+CD25hi Foxp3+T-cells in chronic lymphocytic leukemia
Enhanced formation and survival of CD4+CD25hi Foxp3+T-cells in chronic lymphocytic leukemia
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DOI：
10.1080/10428190902803677
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发表时间：
2009-01-01
影响因子：
2.6
通讯作者：
Van Oers, Marinus H. J.
中科院分区：
文献类型：
--
作者：
Jak, Margot;Mous, Rogier;Van Oers, Marinus H. J.
最近，有报道称慢性淋巴细胞白血病(CLL)患者调节性T(Treg)细胞数量增加。在本研究中，我们分析了CLL中Treg细胞扩张的机制。无论是对CLL患者T细胞受体谱系的分析，还是对Treg细胞CD45亚型表达的分析，都不能证明慢性(肿瘤)抗原刺激是CLL中Treg细胞增殖的可能原因。然而，我们发现了通过CD70共刺激增加Treg细胞形成的证据，因为我们观察到CD40配体激活的CLL细胞(可能被认为是淋巴结CLL细胞的模型)强烈地诱导CD70依赖的Treg细胞的形成。逆转录-多重连接依赖的探针扩增分析34个凋亡调节基因的表达结果显示，与其他CD4+T细胞相比，正常人和CLL患者的Treg细胞都高表达促凋亡的Noxa，低表达抗凋亡的Bcl2。CLL患者Treg细胞的Bcl2表达水平显著高于HD患者。最后，不同的凋亡模式导致了功能水平上的差异，因为CLL患者的Treg细胞比HD患者的Treg细胞对药物诱导的凋亡更具抵抗力。综上所述，CLL中的Treg细胞可能通过CD27-CD70相互作用促进淋巴组织增殖中心的形成增加而积聚，也可能由于Noxa-Bcl2平衡的改变而降低了对凋亡的敏感性。
Recently, it has been described that patients with chronic lymphocytic leukemia (CLL) have increased numbers of regulatory T (Treg) cells. In the present study, we analysed the mechanism behind Treg cells expansion in CLL. Neither analysis of the T-cell receptor repertoire nor CD45 isoform expression of Treg cells from patients with CLL provided evidence for chronic (tumor) antigenic stimulation as a possible cause for Treg cells expansion in CLL. We found evidence however for increased formation of Treg cells via CD70 costimulation, because we observed that CD40 ligand activated CLL cells (which might be considered a model of lymph node CLL cells) strongly induced CD70-dependent formation of Treg cells. Reverse transcription-multiplex ligation-dependent probe amplification assay expression analysis of 34 apoptosis-regulating genes showed that in comparison with other CD4+ T-cells, Treg cells from both healthy individuals (HD) and patients with CLL had a high expression of pro-apoptotic Noxa and a low expression of anti-apoptotic Bcl-2. Strikingly, Bcl-2 levels of Treg cells in patients with CLL were significantly higher than in HD. Finally, the different apoptotic profile resulted in differences at the functional level, because Treg cells from patients with CLL were more resistant to drug-induced apoptosis than Treg cells from HD. In conclusion, Treg cells in CLL may accumulate both by increased formation, facilitated by CD27-CD70 interaction in the lymph node proliferation centres, and decreased sensitivity to apoptosis because of a shifted Noxa-Bcl-2 balance.