Function of miR-146a in Controlling Treg Cell-Mediated Regulation of Th1 Responses

SummaryFoxp3+ regulatory T (Treg) cells maintain immune homeostasis by limiting different types of inflammatory responses. Here, we report that miR-146a, one of the miRNAs prevalently expressed in Treg cells, is critical for their suppressor function. The deficiency of miR-146a in Treg cells resulted in a breakdown of immunological tolerance manifested in fatal IFNγ-dependent immune-mediated lesions in a variety of organs. This was likely due to augmented expression and activation of signal transducer and activator transcription 1 (Stat1), a direct target of miR-146a. Likewise, heightened Stat1 activation in Treg cells subjected to a selective ablation of SOCS1, a key negative regulator of Stat1 phosphorylation downstream of the IFNγ receptor, was associated with analogous Th1-mediated pathology. Our results suggest that specific aspects of Treg suppressor function are controlled by a single miRNA and that an optimal range of Stat1 activation is important for Treg-mediated control of Th1 responses and associated autoimmunity.PaperClip To listen to this audio, enable JavaScript on your browser. However, you can download and play the audio by clicking on the icon belowHelp with MP3 filesOptionsDownload audio (2530 K)

Graphical AbstractFigure optionsDownload high-quality image (255 K)Download as PowerPoint slideHighlights
► Elevated miR-146a expression in Treg cells is crucial for their suppressor function
► Mice harboring miR-146a-deficient Treg cells succumb to IFNγ-mediated autoimmunity
► miR-146a controls Treg-mediated regulation of IFNγ response through targeting Stat1
► Unrestrained Stat1 activation in Treg cells results in IFNγ-mediated Th1 pathology