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

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.