Dasatinib exerts an immunosuppressive effect on CD8+ T cells specific for viral and leukemia antigens
Dasatinib exerts an immunosuppressive effect on CD8+ T cells specific for viral and leukemia antigens
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DOI：
10.1016/j.exphem.2008.05.002
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发表时间：
2008-10-01
影响因子：
2.6
通讯作者：
Schmitt, Michael
中科院分区：
文献类型：
--
作者：
Fei, Fei;Yu, Yingzhe;Schmitt, Michael
目标。研究达沙替尼对CD8(+)T细胞增殖、功能和信号事件的抑制作用。材料与方法。用羧基荧光素二乙酸琥珀酰酯和5-溴-2-脱氧尿苷分别检测达沙替尼处理后CD8(+)T细胞的增殖和细胞周期。采用四聚体染色和ELISPOT法检测健康供者的病毒和白血病抗原特异性CD8(+)T细胞的频率和功能。Western blotting检测达沙替尼和伊马替尼处理后T细胞的T细胞受体（TCR）、核因子κ B （nf - κ B）和Src信号事件。达沙替尼以剂量依赖的方式抑制CD8(+)T细胞的增殖，这与干扰素γ和颗粒酶B的分泌降低以及CD8(+)T细胞在细胞周期G(0)/G(1)期的阻滞有关。与不服用达沙替尼的患者的T细胞状态相比，服用达沙替尼的患者血液样本中CD8(+)T细胞被证明具有抑制作用。Western blotting证实，这些作用是通过下调TCR和nf - κ B信号转导级联分子的磷酸化水平介导的。达沙替尼对Jurkat T细胞Src和TCR信号事件的影响比伊马替尼更有效。我们的研究表明，达沙替尼通过TCR和NF-kappa B信号事件损害cd8t细胞的增殖和功能，而不诱导细胞凋亡。因此，达沙替尼可能改变cd8t细胞维持的同种异体干细胞移植后的移植物抗白血病效应和移植物抗宿主病。达沙替尼也可能被用作一种新的免疫抑制剂。(C) 2008 ISEH -血液与干细胞学会。Elsevier Inc.出版。
Objective. To investigate the inhibitory effects of dasatinib on proliferation, function, and signaling events on CD8(+)T cells.Materials and Methods. Carboxyfluorescein diacetate succinimidyl ester and 5-bromo-2-deoxyuridine were used to detect proliferation and cell cycle of CD8(+)T cells treated with dasatinib, respectively. Frequency and function of viral and leukemia-antigen-specific CD8(+)T cells from healthy donors were measured by tetramer staining and ELISPOT assay. Western blotting analysis was performed to detect T-cell receptor (TCR), nuclear factor kappa B (NF-kappa B) and Src signaling events in T cells treated with dasatinib or imatinib.Results. Dasatinib inhibited proliferation of CD8(+)T cells in a dose-dependent manner, which was associated with lower secretion of interferon-gamma and granzyme B, as well as with arrest of CD8(+)T cells in the G(0)/G(1) phase of cell cycle. Inhibition of CD8(+)T cells was proven for blood samples from a patient under dasatinib medication when compared with their T-cell status without dasatinib. Western blotting confirmed that these effects were mediated through downregulation of the phosphorylation level of molecules from the TCR and the NF-kappa B signaling transduction cascade. Dasatinib proved to be more potent than imatinib on Src and TCR signaling events in Jurkat T cells.Conclusion. Our study demonstrated that dasatinib impaired proliferation and function of CD8'T cells via TCR and NF-kappa B signaling events without inducing apoptosis. Therefore, dasatinib might alter the graft-vs-leukemia effect and the graft-vs-host disease after allogeneic stem cell transplantation sustained by CD8'T cells. Dasatinib might also be used as a novel immunosuppressant agent. (C) 2008 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.