Abstract
By genetic inactivation of key microRNA biogenesis enzymes, we and others have previously demonstrated the critical requirement of the microRNA pathway for the differentiation and function of Foxp3+ regulatory T cells. In this study, we identified members of the miR-17∼92a cluster of microRNAs to be enriched in regulatory T cells. To investigate the function of this microRNA cluster, we deleted the gene specifically in Foxp3+ cells in mice. We found that miR-17∼92a is required for the fitness of regulatory T cells, and deficiency impacted at the level of apoptosis and proliferation of these cells. This led to a loss of Foxp3+ cells over time, particularly in competitive settings, and culminated in a range of immunologic perturbations. Thus, miR-17∼92a-target interactions are part of the essential microRNA networks that safeguard the regulatory T cell lineage.
Highlights
Appropriate regulation of immune responses is critical for ensuring adequate immunity against harmful pathogens without developing uncontrolled inflammation or autoimmunity that lead to tissue damage
By targeted mutagenesis of key miRNA pathway components in mice, we and others previously demonstrated the critical requirement of miRNAs for the Foxp3+ Treg lineage [20,21,22]
In order to identify specific miRNAs that might be important in Tregs, we analyzed the miRNA profiles of T cell lineages that we previously generated by Illumina high throughput sequencing [23,32]
Summary
Appropriate regulation of immune responses is critical for ensuring adequate immunity against harmful pathogens without developing uncontrolled inflammation or autoimmunity that lead to tissue damage. Regulatory T cells (Tregs) suppress the activation and proliferation of other T cells, and play a critical role in maintaining this immunologic homeostasis. Numerous T cells with suppressive activity have been described, but the best characterized are the CD4+CD25+ T cells that express the Forkhead transcription factor Foxp. Expression of Foxp can be induced in naıve CD4+ T cells in response to antigen stimulation in the presence of an appropriate cytokine milieu. Transforming growth factor-b is thought be a key cytokine [6], but retinoic acid may contribute [7,8]. Such ‘‘induced Tregs’’ are prevalent at mucosal surfaces, such as the intestine [9]
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