A Single miRNA-mRNA Interaction Affects the Immune Response in a Context- and Cell-Type-Specific Manner

MicroRNA (miRNA)-dependent regulation of gene expression confers robustness to cellular phenotypes and controls responses to extracellular stimuli. Although a single miRNA can regulate expression of hundreds of target genes, it is unclear whether any of its distinct biological functions can be due to the regulation of a single target. To explore in vivo the function of a single miRNA-mRNA interaction, we mutated the 3′ UTR of a major miR-155 target (SOCS1) to specifically disrupt its regulation by miR-155. We found that under physiologic conditions and during autoimmune inflammation or viral infection, some immunological functions of miR-155 were fully or largely attributable to the regulation of SOCS1, whereas others could be accounted only partially or not at all by this interaction. Our data suggest that the role of a single miRNA-mRNA interaction is dependent on cell type and biological context. •miR-155-mediated SOCS1 repression contributes to Treg cell competitive fitness•Th17 cell generation is independent of SOCS1 regulation by miR-155•CD8+ T cells during chronic but not acute infection need SOCS1 repression by miR-155•NK cell response to MCMV infection requires miR-155-mediated SOCS1 repression A single microRNA (miRNA) can regulate expression of hundreds of target genes, but the biological consequences of individual miRNA-mRNA interactions remain unclear. Rudensky and colleagues show that miR-155-dependent regulation of SOCS1 in different immune cell subsets has cell type- and biological context-dependent in vivo relevance.