Glucocorticoid-induced TNFR-related protein (GITR) ligand modulates cytokine release and NK cell reactivity in chronic lymphocytic leukemia (CLL)
Glucocorticoid-induced TNFR-related protein (GITR) ligand modulates cytokine release and NK cell reactivity in chronic lymphocytic leukemia (CLL)
复制标题
DOI：
10.1038/leu.2011.313
复制
发表时间：
2012-05-01
期刊：
影响因子：
11.4
通讯作者：
Salih, H. R.
中科院分区：
文献类型：
--
作者：
Buechele, C.;Baessler, T.;Salih, H. R.
自然杀伤（NK）细胞在造血系统恶性肿瘤的免疫监视中起着重要作用。它们的反应性受肿瘤表达的NK受体配体介导的激活和抑制信号的影响。肿瘤坏死因子（TNF）家族的许多成员调节肿瘤和免疫效应细胞两者的分化、增殖、活化和死亡。TNF受体家族成员糖皮质激素诱导的TNFR相关蛋白（GITR）刺激小鼠的抗肿瘤免疫，但现有数据表明，GITR可能介导小鼠和男性的不同效应，并损害人NK细胞的反应性。本文对GITR配体（GITRL）在白血病中的表达及功能进行了较为全面的研究。在不同的白血病实体中，在慢性淋巴细胞白血病（CLL）中观察到白血病细胞上GITRL的显著表达，并且与健康对照相比，CLL患者的NK细胞上GITR受体以显著更高的水平表达。在GITR-GITRL相互作用后，经由GITRL进入白血病细胞的信号传导诱导白细胞介素（IL）-6、IL-8和TNF的释放，其充当CLL细胞的生长和存活因子。此外，GITRL损害NK细胞的直接和利妥昔单抗诱导的脱粒、细胞毒性和干扰素-γ产生，这可以通过GITR阻断抗体恢复。因此，GITRL可能有助于疾病病理生理学和对CLL中直接和利妥昔单抗诱导的NK反应性的抗性。
Natural killer (NK) cells play an important role in the immunosurveillance of hematopoietic malignancies. Their reactivity is influenced by activating and inhibitory signals mediated by tumor-expressed ligands for NK receptors. Many members of the tumor necrosis factor (TNF) family modulate differentiation, proliferation, activation and death of both tumor and immune effector cells. The TNF receptor family member glucocorticoid-induced TNFR-related protein (GITR) stimulates anti-tumor immunity in mice, but available data indicate that GITR may mediate different effects in mice and men and impairs the reactivity of human NK cells. Here, we comprehensively studied the expression and function of GITR ligand (GITRL) in leukemia. Among the different leukemia entities, pronounced expression of GITRL on leukemic cells was observed in chronic lymphocytic leukemia (CLL), and the GITR receptor was expressed at significantly higher levels on NK cells of CLL patients compared with healthy controls. Upon GITR-GITRL interaction, signaling via GITRL into the leukemia cells induced the release of interleukin (IL)-6, IL-8 and TNF, which act as growth and survival factors for CLL cells. In addition, GITRL impaired both direct and Rituximab-induced degranulation, cytotoxicity and interferon-gamma production of NK cells, which could be restored by GITR blocking antibodies. Thus, GITRL may contribute to disease pathophysiology and resistance to direct and Rituximab-induced NK reactivity in CLL.