MicroRNA-142 Is Critical for the Homeostasis and Function of Type 1 Innate Lymphoid Cells
MicroRNA-142 Is Critical for the Homeostasis and Function of Type 1 Innate Lymphoid Cells
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DOI：
10.1016/j.immuni.2019.06.016
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发表时间：
2019-09-17
期刊：
影响因子：
32.4
通讯作者：
Fehniger, Todd A.
中科院分区：
文献类型：
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作者：
Berrien-Elliott, Melissa M.;Sun, Yaping;Fehniger, Todd A.
自然杀伤（NK）细胞是1型细胞毒性先天性淋巴细胞（ILC），可抵御病毒并介导抗肿瘤反应，然而控制其发育和功能的机制仍未完全明确。我们假设大量表达的微小RNA - 142（miR - 142）是1型ILC生物学的关键调节因子。白细胞介素 - 15（IL - 15）信号传导诱导miR - 142表达，而全身性和ILC特异性miR - 142缺陷小鼠表现出NK细胞的细胞内在缺失。NK细胞的死亡是由于miR - 142缺陷小鼠中IL - 15受体信号传导减弱所致，可能是通过miR - 142 - 5p对细胞因子信号传导抑制因子1（Socs1）的调节减弱。在Mir142（ - / - ）小鼠中持续存在的ILC显示miR - 142 - 3p靶标αV整合素表达增加，这有助于它们的存活。全身性miR - 142缺陷小鼠表现出ILC1样细胞的扩增，同时转化生长因子 - β（TGF - β）信号传导增加。此外，miR - 142缺陷小鼠的NK细胞依赖性功能降低，对小鼠巨细胞病毒（MCMV）感染的易感性增加。因此，miR - 142关键地整合环境线索，以实现适当的1型ILC内稳态和抵御病毒感染。
Natural killer (NK) cells are cytotoxic type 1 innate lymphoid cells (ILCs) that defend against viruses and mediate anti-tumor responses, yet mechanisms controlling their development and function remain incompletely understood. We hypothesized that the abundantly expressed microRNA-142 (miR-142) is a critical regulator of type 1 ILC biology. Interleukin-15 (IL-15) signaling induced miR-142 expression, whereas global and ILC-specific miR-142-deficient mice exhibited a cell-intrinsic loss of NK cells. Death of NK cells resulted from diminished IL-15 receptor signaling within miR-142-deficient mice, likely via reduced suppressor of cytokine signaling-1 (Socs1) regulation by miR-142-5p. ILCs persisting in Mir142(-/-) mice demonstrated increased expression of the miR-142-3p target alpha V integrin, which supported their survival. Global miR-142-deficient mice exhibited an expansion of ILC1-like cells concurrent with increased transforming growth factor-beta (TGF-beta) signaling. Further, miR-142-deficient mice had reduced NK-cell-dependent function and increased susceptibility to murine cytomegalovirus (MCMV) infection. Thus, miR-142 critically integrates environmental cues for proper type 1 ILC homeostasis and defense against viral infection.