MicroRNA-146a Overexpression Impairs the Positive Selection during T Cell Development

• Published in: Frontiers in immunology 2018-01, Vol.8, p.2006-2006
• Main Authors: Li, Zinan, Zhang, Siya, Wan, Ying, Cai, Menghua, Wang, Weiqing, Zhu, Yuli, Li, Zhen, Hu, Yu, Wang, Huaishan, Chen, Hui, Cui, Lianxian, Zhang, Xuan, Zhang, Jianmin, He, Wei
• Format: Article
• Language: English
• Subjects: Gimap4; Immunology; microRNA-146a; positive selection; T cell development; T cell homeostasis
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2017.02006

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.