A reversible KO model reveals therapeutic potentials of defective Tregs

Tregs must be activated to suppress immune responses, but the transcriptional program controlling Treg activation remains incompletely understood. We previously found that Treg-specific deletion of the chromatin remodeling factor Brg1 impairs Treg activation and causes fatal autoimmunity in mice. Here, using a method that allows gene KO to be reversed in a Tamoxifen-dependent manner, we addressed whether reinstating Brg1 expression in the defective Tregs in the sick mice could restore Treg function, and if so, whether such Tregs could stop and resolve the fatal inflammation. We found that reexpressing Brg1 unexpectedly converted the defective Tregs into highly potent “SuperTregs”, which effectively rescued the dying mice. Remarkably, Brg1 reexpression in as little as 8% of the Tregs sufficed for the rescue in some cases. Brg1 -deleted Tregs in the inflamed mice experienced excessive cytokine stimulation, became hyperactivated upon Brg1 reexpression and then deactivated as the inflammation subsided, suggesting that BRG1 acted in conjunction with inflammation to induce and maintain the SuperTreg phenotype. These data illustrate the power of reversible KO models in uncovering gene functions, and suggest a novel therapeutic strategy for IPEX(-related) disorders that exploits the defective Tregs and the inflammatory environment preexisting within the patients.