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MicroRNA Regulation of Th17 Cell Differentiation

  • Author(s): Montoya, Misty Marie
  • Advisor(s): Hermiston, Michelle
  • et al.
Abstract

MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the post-transcriptional level. They have been shown to play important roles in the development of B and T lymphocytes, and are powerful modulators of mature helper T cell differentiation and function in immunity. The miR-17~92 cluster of miRNAs regulates the differentiation and function of several subsets of T helper cells, including T helper (Th)17 cells. Th17 cells are a subset of CD4 helper T cells that characteristically produce the pro-inflammatory cytokine IL-17. They are defined by expression of the transcription factor RORγt, and are commonly identified by the chemokine receptor CCR6. Th17 cell responses orchestrate immunity against extracellular pathogens, but also underlie autoimmune disease pathogenesis.

We used conditional deletion of the entire cluster and manipulation of individual miRNAs within the cluster to dissect miR-17~92 control of Th17 cells. These experiments uncovered a distinct and critical role for miR-18a in limiting Th17 cell differentiation. In fact, miR-18a was the most dynamically upregulated miRNA in activated T cells among miR-17~92 cluster miRNAs. Targeted deletion of miR-18a enhanced CCR6+RORγt+ Th17 cell differentiation in vitro and increased the frequencies of Th17 cells in the lung expressing CCR6, RORγt and IL-17A in airway inflammation models in vivo. Furthermore, inhibition of miR-18 increased CCR6 and RORγt expression in mouse and human CD4+ T cells, revealing functional conservation. miR-18a directly targeted Smad4, Hif1a, and Rora, all key transcription factors in the Th17 cell gene expression program. Together these findings indicate that activating signals influence the fate of T helper cell differentiation via differential regulation of individual miRNAs within a common cluster.

To expand our work, we also sought to determine the global miRNA regulation of Th17 cell differentiation. Using a reliable and reproducible screening method in primary T cells, we examined the scope of miRNA regulators of both mouse and human Th17 cells. Our work supported previously identified miRNAs known to modulate Th17 cells and importantly revealed new miRNAs that both enhance and inhibit Th17 cells. These exciting results open opportunities for new projects to define the specifics of their biology.

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