Nfil3-independent lineage maintenance and antiviral response of natural killer cells.-猫眼课题宝

DOI：

10.1084/jem.20130417

发表时间：

2013-12-16

期刊：

The Journal of experimental medicine

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Firth MA;Madera S;Beaulieu AM;Gasteiger G;Castillo EF;Schluns KS;Kubo M;Rothman PB;Vivier E;Sun JC

来源链接：

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865482/?report=classic

在缺乏转录因子 Nfil3 的情况下，炎症细胞因子会驱动 NK 细胞扩增，而 Nfil3 对于成熟 NK 细胞的维持和功能是不可或缺的。自然杀伤 (NK) 细胞谱系的发育依赖于转录因子 Nfil3（或 E4BP4），该因子被认为在 IL-15 信号传导的下游发挥作用。 Nfil3 缺陷小鼠缺乏 NK 细胞，而其他淋巴细胞谱系（B、T 和 NKT 细胞）基本保持完整。我们报告了感染小鼠巨细胞病毒（MCMV）或表达病毒 m157 糖蛋白的重组病毒的 Nfil3−/− 小鼠中表达 Ly49H 的 NK 细胞的出现。就 IFN-γ 产生和细胞毒性而言，处于抗原驱动扩增峰值的 Nfil3−/− NK 细胞在功能上与来自受感染野生型小鼠的 NK 细胞相似，并且可以类似地产生在淋巴和非淋巴组织中持续存在 >60 天的长寿命记忆 NK 细胞。我们证明 NK 细胞记忆的生成和维持是一个独立于 Nfil3 但依赖于 IL-15 的过程。此外，骨髓中未成熟 NK 细胞或成熟外周 NK 细胞中 Nfil3 的特异性消除对 NK 细胞谱系维持或稳态没有明显影响。因此，Nfil3的表达仅在NK细胞发育的早期至关重要，并且在病毒感染期间通过激活受体和促炎细胞因子发出的信号可以绕过对Nfil3的需求，促进病毒特异性NK细胞的增殖和长期存活。

Inflammatory cytokines drive NK cell expansion in the absence of the transcription factor Nfil3, and Nfil3 is dispensable for the maintenance and function of mature NK cells. Development of the natural killer (NK) cell lineage is dependent on the transcription factor Nfil3 (or E4BP4), which is thought to act downstream of IL-15 signaling. Nfil3-deficient mice lack NK cells, whereas other lymphocyte lineages (B, T, and NKT cells) remain largely intact. We report the appearance of Ly49H-expressing NK cells in Nfil3−/− mice infected with mouse cytomegalovirus (MCMV) or recombinant viruses expressing the viral m157 glycoprotein. Nfil3−/− NK cells at the peak of antigen-driven expansion were functionally similar to NK cells from infected wild-type mice with respect to IFN-γ production and cytotoxicity, and could comparably produce long-lived memory NK cells that persisted in lymphoid and nonlymphoid tissues for >60 d. We demonstrate that generation and maintenance of NK cell memory is an Nfil3-independent but IL-15–dependent process. Furthermore, specific ablation of Nfil3 in either immature NK cells in the bone marrow or mature peripheral NK cells had no observable effect on NK cell lineage maintenance or homeostasis. Thus, expression of Nfil3 is crucial only early in the development of NK cells, and signals through activating receptors and proinflammatory cytokines during viral infection can bypass the requirement for Nfil3, promoting the proliferation and long-term survival of virus-specific NK cells.