H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL 33612, USA.
J Immunol. 2010 Nov 15;185(10):6058-67. doi: 10.4049/jimmunol.1001682. Epub 2010 Oct 13.
NK cells are major effectors of the innate immune response through cytolysis and bridge to the adaptive immune response through cytokine release. The mediators of activation are well studied; however, little is known about the mechanisms that restrain activation. In this report, we demonstrate that the transcriptional repressor PRDM1 (also known as Blimp-1 or PRDI-BF1) is a critical negative regulator of NK function. Three distinct PRDM1 isoforms are selectively induced in the CD56(dim) NK population in response to activation. PRDM1 coordinately suppresses the release of IFN-γ, TNF-α, and TNF-β through direct binding to multiple conserved regulatory regions. Ablation of PRDM1 expression leads to enhanced production of IFN-γ and TNF-α but does not alter cytotoxicity, whereas overexpression blocks cytokine production. PRDM1 response elements are defined at the IFNG and TNF loci. Collectively, these data demonstrate a key role for PRDM1 in the negative regulation of NK activation and position PRDM1 as a common regulator of the adaptive and innate immune response.
自然杀伤 (NK) 细胞通过细胞溶解作用成为先天免疫反应的主要效应细胞，并通过细胞因子释放作用与适应性免疫反应相联系。激活的介质已得到很好的研究；然而，关于抑制激活的机制知之甚少。在本报告中，我们证明转录抑制因子 PRDM1（也称为 Blimp-1 或 PRDI-BF1）是 NK 功能的关键负调控因子。三种不同的 PRDM1 异构体在 CD56(dim) NK 群体中被选择性诱导，以响应激活。PRDM1 通过直接结合多个保守调节区，协调抑制 IFN-γ、TNF-α 和 TNF-β 的释放。PRDM1 表达的缺失导致 IFN-γ 和 TNF-α 的产生增加，但不改变细胞毒性，而过表达则阻断细胞因子的产生。IFNG 和 TNF 基因座上定义了 PRDM1 反应元件。总之，这些数据表明 PRDM1 在 NK 激活的负调控中起关键作用，并将 PRDM1 定位为适应性和先天免疫反应的共同调节因子。
