DEPTOR modulates activation responses in CD4⁺ T cells and enhances immunoregulation following transplantation

DEPTOR is an evolutionarily conserved cell-intrinsic binding partner of mTOR that functions as a negative regulator of signaling responses. In this study, we show that DEPTOR is expressed within CD4⁺ T cells, and we observed that its relative level of expression modulates differentiation as well as glucose utilization within CD4⁺ T effectors in vitro. Using knock-in mice, we also find that induced expression of DEPTOR within CD4⁺ T regulatory cells stabilizes Foxp3 expression, shifts metabolism toward oxidative phosphorylation, and increases survival and suppressive function. In vivo, fully MHC mismatched cardiac allograft survival is significantly prolonged in knock-in recipients and sustained recipient expression of DEPTOR in combination with costimulatory blockade induces long-term graft survival. Furthermore, we show that the induced expression of DEPTOR in CD4⁺ T effectors fails to inhibit acute allograft rejection. Rather, prolonged survival is dominantly mediated via induced expression and function of DEPTOR within recipient CD4⁺ T regulatory cells. These collective findings identify DEPTOR as a novel protein that functions in CD4⁺ T cells to augment immunoregulation in vitro and in vivo.