MicroRNAs (miRNAs) have emerged as important and nearly ubiquitous regulators of gene expression in multicellular eukaryotes. Although they mediate only modest repression of each of their direct mRNA targets, miRNAs have surprisingly powerful effects in a wide variety of biological processes. In helper T cells, the miRNA pathway is required for robust proliferation, survival, differentiation and cytokine production. With over 1000 distinct human miRNAs discovered in the past decade, the current challenge is to identify the particular miRNAs that operate in helper T cells and integrate them into the regulatory networks that determine their cell fate decisions and effector functions.

We use functional rescue screens to identify miRNAs that inhibit or enhance the differentiation of T helper cell subsets and their production of effector cytokines. This approach has uncovered novel regulatory circuits that influence Th1, Th2, and Th17 cell responses. Combined bioinformatic, biochemical, and gene expression analyses reveal the direct targets of functionally relevant miRNAs and dysregulated programs of gene expression downstream of these targets. Systematic interrogation of the functional roles of direct targets reveals regulatory networks coordinated by miRNA action, and demonstrates how the co-evolution of miRNAs and their target genes can be exploited to discover unexpected genes and pathways that regulate cytokine production.

Funding: NIH R01HL109102, P01HL107202, U19CA179512; Dana Foundation; Leukemia & Lymphoma Society