PRDM1 decreases sensitivity of human NK cells to IL2‐induced cell expansion by directly repressing CD25 (IL2RA),Journal of Leukocyte Biology

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PRDM1 decreases sensitivity of human NK cells to IL2‐induced cell expansion by directly repressing CD25 (IL2RA)
Journal of Leukocyte Biology ( IF 3.6 ) Pub Date : 2020-11-04 , DOI: 10.1002/jlb.2a0520-321rr
Burcu Akman _{1,

2} , Xiaozhou Hu ₁ , Xuxiang Liu ₃ , Tevfik Hatipoğlu _{1,

2} , Hua You ₄ , Wing C Chan ₃ , Can Küçük _{1,

2,

5}

Affiliation

IL2 receptor signaling is crucial for human NK cell activation and gain of effector functions. The molecular mechanisms involved in termination of IL2 activation are largely unknown in human NK cells. PR/SET domain 1 was previously reported to decrease cell growth and increase apoptosis in an IL2‐dependent manner in malignant NK cell lines, suggesting the possibility of down‐regulation of IL2 signaling pathway gene(s) through direct transcriptional repression. Using ChIP‐Seq, we identified a PRDM1 binding site on the first intron of CD25 (IL2RA), which codes for the IL2 receptor subunit regulating sensitivity to IL2 signaling, in primary NK cells activated with engineered K562 cells or IL2. Ectopic expression of PRDM1 down‐regulated CD25 expression at transcript and protein levels in two PRDM1 nonexpressing NK cell lines. shRNA‐mediated knockdown of CD25 in two malignant NK cell lines led to progressive depletion of NK cells in low IL2 concentrations. By contrast, ectopic CD25 expression in primary human NK cells led to progressive increase in cell number in CD25‐transduced cells in low IL2 concentrations. Altogether these results reveal a pivotal role of PRDM1 in inhibition of IL2‐induced NK cell expansion through direct repression of CD25 in activated human NK cells. These observations provide additional support for the role of PRDM1 in attenuation of NK cell activation and growth, with implications on neoplastic transformation or NK cell function when it is deregulated.

中文翻译：

PRDM1 通过直接抑制 CD25 (IL2RA) 降低人类 NK 细胞对 IL2 诱导的细胞扩增的敏感性

IL2 受体信号传导对于人类 NK 细胞的激活和效应功能的获得至关重要。在人类 NK 细胞中，终止 IL2 激活的分子机制在很大程度上是未知的。此前有报道称，PR/SET 结构域 1 在恶性 NK 细胞系中以 IL2 依赖性方式减少细胞生长并增加细胞凋亡，表明可能通过直接转录抑制下调 IL2 信号通路基因。使用 ChIP-Seq，我们在用工程 K562 细胞或 IL2 激活的原代 NK 细胞中鉴定了CD25 ( IL2RA ) 第一个内含子上的 PRDM1 结合位点，该内含子编码调节对 IL2 信号传导敏感性的 IL2 受体亚基。在两种不表达 PRDM1 的 NK 细胞系中，PRDM1 的异位表达在转录物和蛋白质水平上下调 CD25 的表达。 shRNA 介导的两种恶性 NK 细胞系中 CD25 的敲低导致 NK 细胞在低 IL2 浓度下逐渐耗竭。相比之下，原代人 NK 细胞中的异位 CD25 表达导致低 IL2 浓度下 CD25 转导细胞的细胞数量逐渐增加。总之，这些结果揭示了 PRDM1 通过直接抑制活化的人 NK 细胞中的 CD25，在抑制 IL2 诱导的 NK 细胞扩增中发挥关键作用。这些观察结果为 PRDM1 在减弱 NK 细胞活化和生长中的作用提供了额外的支持，当它失调时，会对肿瘤转化或 NK 细胞功能产生影响。

更新日期：2020-11-04

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