MicroRNAs 24 and 27 Suppress Allergic Inflammation and Target a Network of Regulators of T Helper 2 Cell-Associated Cytokine Production

MicroRNAs (miRNAs) are important regulators of cell fate decisions in immune responses. They act by coordinate repression of multiple target genes, a property that we exploited to uncover regulatory networks that govern T helper-2 (Th2) cells. A functional screen of individual miRNAs in primary T cells uncovered multiple miRNAs that inhibited Th2 cell differentiation. Among these were miR-24 and miR-27, miRNAs coexpressed from two genomic clusters, which each functioned independently to limit interleukin-4 (IL-4) production. Mice lacking both clusters in T cells displayed increased Th2 cell responses and tissue pathology in a mouse model of asthma. Gene expression and pathway analyses placed miR-27 upstream of genes known to regulate Th2 cells. They also identified targets not previously associated with Th2 cell biology which regulated IL-4 production in unbiased functional testing. Thus, elucidating the biological function and target repertoire of miR-24 and miR-27 reveals regulators of Th2 cell biology. [Display omitted] •Multiple individual miRNAs inhibit Th2 cell differentiation and function•miR-24 and miR-27 limit IL-4 production in T cells•Mice lacking miR-24 and miR-27 in T cells have enhanced Th2 cell responses•miR-24 and miR-27 inhibit a network of direct targets that regulate IL-4 production MicroRNAs (miRNAs) are important regulators of cell fate decisions in immune responses. Ansel and colleagues identify miR-24 and miR-27 as inhibitors of Th2 cell differentiation and function and use miRNA-directed pathway discovery to elucidate a gene network upstream of interleukin-4 production in T cells.