Heat Shock Protein 90 Is Critical for Regulation of Phenotype and Functional Activity of Human T Lymphocytes and NK Cells
Heat Shock Protein 90 Is Critical for Regulation of Phenotype and Functional Activity of Human T Lymphocytes and NK Cells
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DOI：
10.4049/jimmunol.1200593
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发表时间：
2013-02-01
影响因子：
4.4
通讯作者：
Munshi, Nikhil C.
中科院分区：
文献类型：
--
作者：
Bae, Jooeun;Munshi, Aditya;Munshi, Nikhil C.
90 kDa热休克蛋白(Hsp90)已经成为一种重要的治疗靶点，目前正在对一些恶性肿瘤进行评估。虽然Hsp90抑制剂具有较高的治疗指数，对正常细胞的作用有限，但已被描述为抑制树突状细胞的功能。然而，它对人类免疫效应细胞的影响可能具有重要的临床意义，但仍未被探索。在这项研究中，我们评估了抑制Hsp90对人T淋巴细胞和NK细胞的影响，包括它们的抗原表达、激活、增殖和功能活性。这些研究表明，抑制Hsp90可逆地下调T淋巴细胞表面关键抗原(CD3、CD4、CD8)、共刺激分子(CD28、CD40L)和ab受体的表达，以及激活NK细胞上的受体(CD2、CD11a、CD94、NKp30、NKp44、NKp46、KARp50.3)。抑制HSP90可显著降低T淋巴细胞表面和细胞内的CD4蛋白表达，这与其对Src-kinasep56(Lck)的异常调控有关。Hsp90抑制CD3(+)T淋巴细胞和CD8(+)T细胞亚群所触发的AGS的下调与其细胞激活、增殖和/或干扰素-γ产生的干扰有关，无论这种抑制发生在激活或灭活的细胞中。此外，在抑制Hsp90后，NK细胞上关键激活受体的下调导致对肿瘤细胞的细胞毒作用降低。因此，这些观察结果表明，需要密切监测接受Hsp90抑制剂治疗的患者的免疫功能，并可能为自身免疫性疾病提供潜在的治疗应用。免疫学杂志，2013,190：1360-1371。
The 90-kDa heat shock protein (Hsp90) has become an important therapeutic target with ongoing evaluation in a number of malignancies. Although Hsp90 inhibitors have a high therapeutic index with limited effects on normal cells, they have been described to inhibit dendritic cell function. However, its effect on human immune effector cells may have significant clinical implications, but remains unexplored. In this study, we have evaluated the effects of Hsp90 inhibition on human T lymphocyte and NK cells, including their Ag expression, activation, proliferation, and functional activities. These studies demonstrate that Hsp90 inhibition irreversibly downregulates cell surface expression of critical Ags (CD3, CD4, CD8), the costimulatory molecule (CD28, CD40L), and ab receptors on T lymphocytes, as well as activating receptors (CD2, CD11a, CD94, NKp30, NKp44, NKp46, KARp50.3) on NK cells. Hsp90 inhibition significantly reduced CD4 protein expression on T lymphocytes at both the cell surface and intracellular level, which was shown to be associated with aberrant regulation of Src-kinase p56(Lck). Downregulation of the Ags triggered by Hsp90 inhibition on CD3(+) T lymphocytes, both in CD4(+) and CD8(+) T cell subsets, was associated with a disruption in their cellular activation, proliferation, and/or IFN-gamma production, when the inhibition occurred either in activated or inactivated cells. In addition, downregulation of key activating receptors on NK cells following Hsp90 inhibition resulted in decreased cytotoxicity against tumor cells. Therefore, these observations demonstrate the need to closely monitor immune function in patients being treated with a Hsp90 inhibitor and may provide a potential therapeutic application in autoimmune diseases. The Journal of Immunology, 2013, 190: 1360-1371.