Blimp-1 impairs T cell function via upregulation of TIGIT and PD-1 in patients with acute myeloid leukemia.
Blimp-1 impairs T cell function via upregulation of TIGIT and PD-1 in patients with acute myeloid leukemia.
复制标题
Blimp-1 通过上调急性髓系白血病患者的 TIGIT 和 PD-1 损害 T 细胞功能
DOI：
10.1186/s13045-017-0486-z
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发表时间：
2017-06-19
影响因子：
28.5
通讯作者：
Zheng H
中科院分区：
文献类型：
--
作者：
Zhu L;Kong Y;Zhang J;Claxton DF;Ehmann WC;Rybka WB;Palmisiano ND;Wang M;Jia B;Bayerl M;Schell TD;Hohl RJ;Zeng H;Zheng H
背景T细胞免疫球蛋白和免疫受体酪氨酸基抑制基序（ITIM）结构域（TIGIT）和程序性细胞死亡蛋白1（PD-1）是与急性髓系白血病（AML）T细胞耗竭相关的重要抑制性受体。在这项研究中，我们的目的是确定潜在的转录机制调节这些抑制途径。具体而言，我们研究了转录因子B淋巴细胞诱导的成熟蛋白1（Blimp-1）在T细胞反应和TIGIT和PD-1的转录调控AML. MethodsPeripheral blood samples收集AML患者在这项研究中的作用。流式细胞术检测Blimp-1表达。分析Blimp-1表达与AML患者临床特征的相关性。使用基于流式细胞术的测定进行Blimp-1表达T细胞的表型和功能研究。应用荧光素酶报告基因测定和ChIP测定来评估Blimp-1的直接结合和转录活性。使用siRNA沉默Blimp-1，我们进一步阐明了Blimp-1在TIGIT和PD-1表达和T细胞免疫应答中的调节作用。与耗竭一致，Blimp-1 + T细胞上调多种抑制性受体，包括PD-1和TIGIT。此外，它们在功能上受损，表现为细胞因子产生低和细胞毒性能力降低。重要的是，通过siRNA敲低抑制Blimp-1来逆转功能缺陷。此外，Blimp-1结合PD-1和TIGIT的启动子，并积极调节其expression. ConclusionsOur study demonstrates a important inhibitory effect of Blimp-1 on T cell response in AML; thus，targeting Blimp-1 and its regulated molecules to improve immune response may provide effective leukemia therapeutics.
BackgroundT cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) and programmed cell death protein 1 (PD-1) are important inhibitory receptors that associate with T cell exhaustion in acute myeloid leukemia (AML). In this study, we aimed to determine the underlying transcriptional mechanisms regulating these inhibitory pathways. Specifically, we investigated the role of transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) in T cell response and transcriptional regulation of TIGIT and PD-1 in AML.MethodsPeripheral blood samples collected from patients with AML were used in this study. Blimp-1 expression was examined by flow cytometry. The correlation of Blimp-1 expression to clinical characteristics of AML patients was analyzed. Phenotypic and functional studies of Blimp-1-expressing T cells were performed using flow cytometry-based assays. Luciferase reporter assays and ChIP assays were applied to assess direct binding and transcription activity of Blimp-1. Using siRNA to silence Blimp-1, we further elucidated the regulatory role of Blimp-1 in the TIGIT and PD-1 expression and T cell immune response.ResultsBlimp-1 expression is elevated in T cells from AML patients. Consistent with exhaustion, Blimp-1+T cells upregulate multiple inhibitory receptors including PD-1 and TIGIT. In addition, they are functionally impaired manifested by low cytokine production and decreased cytotoxicity capacity. Importantly, the functional defect is reversed by inhibition of Blimp-1 via siRNA knockdown. Furthermore, Blimp-1 binds to the promoters of PD-1 and TIGIT and positively regulates their expression.ConclusionsOur study demonstrates an important inhibitory effect of Blimp-1 on T cell response in AML; thus, targeting Blimp-1 and its regulated molecules to improve the immune response may provide effective leukemia therapeutics.