MicroRNA-146a Overexpression Impairs the Positive Selection during T Cell Development.
MicroRNA-146a Overexpression Impairs the Positive Selection during T Cell Development.
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Microrna-146a 过度表达会损害 T 细胞发育过程中的正选择
DOI：
10.3389/fimmu.2017.02006
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发表时间：
2017
影响因子：
7.3
通讯作者：
He W
中科院分区：
文献类型：
--
作者：
Li Z;Zhang S;Wan Y;Cai M;Wang W;Zhu Y;Li Z;Hu Y;Wang H;Chen H;Cui L;Zhang X;Zhang J;He W
microrna在调节免疫系统中起着至关重要的作用。miR-146a是NF-κB信号的有效反馈抑制因子，在敲除小鼠模型中被证明限制先天免疫反应和骨髓生成。在这里，我们在miR-146a转基因小鼠模型中观察到高淋巴生成表现为轻度脾肿大和严重淋巴结病。过表达miR-146a导致T细胞增殖增强，凋亡减少。即使在生理条件下，转基因小鼠的CD4+ T细胞或效应记忆T细胞的活化程度也更高。重要的是，作为产生中枢耐受的关键步骤之一，在转基因小鼠中胸腺细胞的阳性选择受到损害，导致CD4+CD8+双阳性胸腺细胞增多，而CD4+CD8 -和CD4 - CD8+单阳性胸腺细胞减少。选择的CD4 - CD8+胸腺细胞的成熟也受到损害，导致转基因小鼠胸腺中CD4 - CD8+胸腺细胞比CD4+CD8 -胸腺细胞损失更严重。基因表达谱分析发现9个阳性选择相关基因在转基因小鼠中下调，包括编码主要组织相容性复合体I/II类分子、IL-7受体α链和Gimap4的基因，这些基因的下调可能导致阳性选择受损。Gimap4被证实是miR-146a的新靶点。这些发现进一步扩展了我们对miR-146a在T细胞生物学中的功能的理解，并确定了T细胞发育过程中正选择的一种新的调控机制。
MicroRNAs play crucial roles in modulating immune system. miR-146a, a potent feedback suppressor of NF-κB signaling, was shown to limit the innate immune response and myelopoiesis in a knockout mouse model. Here, we observed high lymphopoiesis demonstrated as mild splenomegaly and severe lymphadenopathy in a miR-146a transgenic mouse model. Overexpression of miR-146a resulted in enhanced proliferation and reduced apoptosis of T cells. More activated CD4+ T cells or effector memory T cells were observed in transgenic mice even under physiological conditions. Importantly, as one of the key steps to generate central tolerance, the positive selection of thymocytes is impaired in transgenic mice, resulting in more CD4+CD8+ double-positive thymocytes but fewer CD4+CD8− and CD4−CD8+ single-positive thymocytes. The maturation of selected CD4−CD8+ thymocytes was also impaired, leading to more severe loss of CD4−CD8+ than CD4+CD8− thymocytes in thymus of transgenic mice. Gene expression profiling analysis identified nine positive selection-associated genes, which were downregulated in transgenic mice, including genes encoding major histocompatibility complex class I/II molecules, IL-7 receptor α chain, and Gimap4, whose downregulation may contribute to the impairment of positive selection. Gimap4 was verified as a novel target of miR-146a. These findings further extend our understanding of the function of miR-146a in T cell biology and identify a novel regulatory mechanism underlying the positive selection during T cell development.