The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Blood. 2011 Feb 10;117(6):1869-79. doi: 10.1182/blood-2010-08-303123. Epub 2010 Dec 3.
Natural killer (NK) cells are innate lymphocytes capable of immediate effector functions including cytokine production and cytotoxicity. Compared with B and T cells, the factors that control the peripheral maturation of NK cells are poorly understood. We show that Blimp1, a transcriptional repressor required for the differentiation of plasma cells and short-lived effector T cells, is expressed by NK cells throughout their development. Interleukin 15 (IL-15) is required for the early induction of Blimp1 in NK cells, with expression increasing in the most mature subsets of mouse and human NK cells. We show that Blimp1 is required for NK-cell maturation and homeostasis and for regulating their proliferative potential. It is also essential for high granzyme B expression, but not for most cytokine production and cytotoxicity. Surprisingly, interferon regulatory factor 4 (IRF4) and B-cell lymphoma 6 (Bcl6), 2 transcription factors crucial for the regulation of Blimp1 in B and T cells, are largely dispensable for Blimp1 expression in NK cells. T-bet deficiency, however, leads to attenuated Blimp1 expression. We have identified NK cells as the first hematopoietic cell type in which the IRF4-Blimp1-Bcl6 regulatory axis is not in operation, highlighting the distinct nature of the NK-cell gene-regulatory network.
自然杀伤 (NK) 细胞是先天淋巴细胞,能够立即发挥效应功能,包括细胞因子产生和细胞毒性。与 B 和 T 细胞相比,控制 NK 细胞外周成熟的因素知之甚少。我们表明,Blimp1 是一种转录抑制剂,对于浆细胞和短暂效应 T 细胞的分化是必需的,在 NK 细胞的整个发育过程中都有表达。白细胞介素 15 (IL-15) 是 NK 细胞中早期诱导 Blimp1 的必需因子,在小鼠和人类 NK 细胞的最成熟亚群中表达增加。我们表明,Blimp1 是 NK 细胞成熟和稳态所必需的,并且调节其增殖潜能。它对于高颗粒酶 B 的表达也是必需的,但对于大多数细胞因子的产生和细胞毒性则不是必需的。令人惊讶的是,干扰素调节因子 4 (IRF4) 和 B 细胞淋巴瘤 6 (Bcl6),这两种在 B 和 T 细胞中调节 Blimp1 的转录因子,在 NK 细胞中表达 Blimp1 时则很大程度上是可有可无的。然而,T 细胞因子缺陷导致 Blimp1 表达减弱。我们已经确定 NK 细胞是第一个造血细胞类型,其中 IRF4-Blimp1-Bcl6 调节轴不起作用,突出了 NK 细胞基因调控网络的独特性质。
Adv Exp Med Biol. 2011
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