MicroRNA regulation of helper T cell differentiation and immune effector functions

CD4+ T helper cells are central orchestrators of the immune response. They can amplify or dampen the intensity of inflammation, activate and recruit other immune cells, and help B cells to make high affinity antibodies. We study multiple functionally distinct subsets of T helper cells including Th1, Th2, Th17, and Tfh cells. Cytokines direct the differentiation of these different types of helper T cells, and selective cytokine secretion is also the major mode of helper T cell effector function.

T cell subsets

 

MicroRNAs (miRNAs) are small endogenously expressed non-coding RNAs that modulate programs of gene expression through the inhibition of target messenger transcripts (mRNA). Naive CD4+ T cells that cannot produce miRNAs exhibit reduced cell division and survival in response to immune stimuli. Surprisingly, they also undergo aberrantly rapid, unrestrained differentiation into effector cells.  

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Using a technology that allows for rapid screening of individual miRNAs in primary T cells, we have identified multiple individual miRNAs and miRNA clusters that inhibit or enhance T helper cell differentiation. We found that miR-29 inhibits IFN╬│ production and Th1 differentiation through targeting the transcription factors T-bet and Eomes. We  also demonstrated that the miR-17~92 miRNA cluster is required for robust Tfh cell differentiation, and identified miR-19 as an enhancer of Th2 function.

miRNA Targets

As regulators of networks of target genes, miRNAs offer the potential to identify novel molecular pathways important for the differentiation and function of T helper cells. We aim to develop tools and technologies using RNA sequencing and other biochemical approaches to further define these miRNA-regulated networks. Ultimately, we hope that miRNA and miRNA-regulated networks will provide novel therapeutic targets for immunologic diseases.