Genetically modifying the RNA-binding protein Regnase-1 reveals its critical role in Treg homeostasis and functions in vivo

But how and by what mechanisms Regnase-1 controls Foxp3+ Tregs in vivo remains poorly studied. Here we generated a conditional knock-in mouse in which a degradation-resistant Regnase-1 mutant (R111A) was selectively expressed in Foxp3+ Tregs as a transgene (Foxp3YFP-CreLSL-R111Afl/fl) to investigate the roles of Regnase-1 in Tregs.

We found that all male Foxp3YFP-CreLSL-R111Afl/fl mice died of fatal autoimmune diseases by 4 weeks of age, which was accompanied by massive activation of T effector cells in vivo. We also found that the Foxp3+ Tregs in male Foxp3YFP-CreLSL-R111Afl/fl mice were depleted in the periphery, but not Tregs in the thymus. Further analyses revealed that the Foxp3+ Tregs expressing the Regnase-1 mutant R111A displayed an intrinsic survival defect and that transferring wild type Foxp3+ Tregs into the young male Foxp3YFP-CreLSL-R111Afl/fl mice could rescue the lethal autoimmune phenotype.