Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, California, United States of America.
Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, California, United States of America.
PLoS Biol. 2022 Feb 18;20(2):e3001552. doi: 10.1371/journal.pbio.3001552. eCollection 2022 Feb.
Regulatory T (Treg) cells are critical in preventing aberrant immune responses. Posttranscriptional control of gene expression by microRNA (miRNA) has recently emerged as an essential genetic element for Treg cell function. Here, we report that mice with Treg cell-specific ablation of miR-142 (hereafter Foxp3CremiR-142fl/fl mice) developed a fatal systemic autoimmune disorder due to a breakdown in peripheral T-cell tolerance. Foxp3CremiR-142fl/fl mice displayed a significant decrease in the abundance and suppressive capacity of Treg cells. Expression profiling of miR-142-deficient Treg cells revealed an up-regulation of multiple genes in the interferon gamma (IFNγ) signaling network. We identified several of these IFNγ-associated genes as direct miR-142-3p targets and observed excessive IFNγ production and signaling in miR-142-deficient Treg cells. Ifng ablation rescued the Treg cell homeostatic defect and alleviated development of autoimmunity in Foxp3CremiR-142fl/fl mice. Thus, our findings implicate miR-142 as an indispensable regulator of Treg cell homeostasis that exerts its function by attenuating IFNγ responses.
调节性 T（Treg）细胞对于防止异常免疫反应至关重要。微小 RNA（miRNA）对基因表达的转录后调控最近被认为是 Treg 细胞功能的一个重要遗传要素。在这里，我们报告说，Treg 细胞特异性缺失 miR-142 的小鼠（以下简称 Foxp3CremiR-142fl/fl 小鼠）由于外周 T 细胞耐受的破坏而发展为致命的全身性自身免疫性疾病。Foxp3CremiR-142fl/fl 小鼠的 Treg 细胞丰度和抑制能力显著下降。miR-142 缺陷型 Treg 细胞的表达谱分析显示，干扰素 γ（IFNγ）信号网络中的多个基因上调。我们鉴定出这些 IFNγ 相关基因中的几个是 miR-142-3p 的直接靶基因，并观察到 miR-142 缺陷型 Treg 细胞中 IFNγ 的过度产生和信号转导。Ifng 缺失挽救了 miR-142 缺陷型 Treg 细胞的稳态缺陷，并缓解了 Foxp3CremiR-142fl/fl 小鼠自身免疫的发展。因此，我们的研究结果表明，miR-142 是 Treg 细胞稳态的不可或缺的调节因子，通过减弱 IFNγ 反应来发挥其功能。
