miR-143/145 inhibits Th9 cell differentiation by targeting NFATc1

• Published in: Molecular immunology 2021-04, Vol.132, p.184-191
• Main Authors: Qiu, Xin, Shi, Qiuyue, Huang, Youyi, Jiang, Haixing, Qin, Shanyu
• Format: Article
• Language: English
• Subjects: Animals; CD4-Positive T-Lymphocytes - physiology; Cell Differentiation - genetics; Cells, Cultured; Down-Regulation - genetics; Gene Expression Regulation - genetics; Mice; Mice, Inbred C57BL; MicroRNAs - immunology; miR-143; miR-145; NFATC Transcription Factors - genetics; NFATc1; Signal Transduction - genetics; T-Lymphocytes, Helper-Inducer - physiology; Th9 cell; Up-Regulation - genetics
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2021.01.001

•miR-143/145 expression decreases gradually during the differentiation process of Th9 cells.•miR-143/145 inhibits Th9 cell differentiation.•NFATc1 is a direct common target of miR-143/145 in T cells.•Downregulation of NFATc1 inhibits Th9 cell differentiation.•Overexpression of NFATc1 reversed inhibitory effects of miR-143/145 on Th9 cell. Th9 cells are a defined CD4+ helper T cell subgroup found to promote or suppress oncogenesis in a context-dependent manner. How microRNAs (miRNAs) shape Th9 cell functionality, however, remains to be studied. Herein, we determined that miR-143/145 is downregulated during Th9 differentiation. When these miRNAs were upregulated, this inhibited Th9 differentiation, proliferation, and IL-9 production. Overexpressing miR-143/145 in Th9 cells further suppressed NFATc1 expression at the protein and mRNA level, whereas the opposite phenotype was observed when miR-143/145 was downregulated in these cells. NFATc1 silencing markedly inhibited Th9 cell differentiation, whereas overexpressing this transcription factor was sufficient to reverse miR-143/145-associated phenotypes in these cells. These findings thus indicate that the ability of miR-143/145 to inhibit Th9 cell differentiation is attributable to their ability to target and suppress NFATc1 expression. Overall, our results highlight a novel mode of action whereby miR-143/145 controls Th9 differentiation, suggesting that this pathway may be amenable to therapeutic targeting in the context of anti-cancer treatment in the future.