From molecules to mothers: Regulatory T cell transcriptional regulation and control of immune responses

Regulatory T (Treg) cells are critical for control of immune responses and thus maintenance of immune homeostasis in a variety of inflammatory conditions. The transcription factor Foxp3 is necessary and sufficient for Treg cell lineage development both in the thymus and the periphery and their ability to suppress immune responses. Deficiency of Foxp3 or Treg regulation results in widespread inflammation in mice and humans highlighting its essential role. However, how Treg cells function to limit inflammation in a variety of settings is poorly understood. The work described herein attempts in three studies to elucidate some of the details of how and where regulatory T cells function. In the gut, IL-10 activation of STAT3 signalling is shown to be essential for Treg cell control of Th17 inflammation and a resulting colitis suggesting that Tregs respond to and amplify existing negative regulatory circuits. Using DNase-seq and ChIP-seq Foxp3 is shown to predominantly utilize preexisting or TCR-signalling driven enhancers supporting a model of Foxp3 exploitation of a preformed enhancer landscape in order to direct Treg cell differentiation and function. Lastly, extra-thymically generated Treg cells are shown to be important for maternal fetal tolerance and the mechanisms necessary for their differentiation appear to have evolved in placental mammals. Taken together, these studies provide further insight into regulatory T cell function and offer the potential for therapeutic development in a variety of disease settings.