Adoptive transfer of regulatory T cells (Tregs) has been shown to improve alloengraftment in animal models. However, it is technically challenging to expand Tregs ex vivo for the purpose of infusing large numbers of cells in the clinic. We demonstrated an innovative approach to engineer an orthogonal IL-2-IL-2 receptor (IL-2R) pair that selectively interacts with each other and transmits native IL-2 signals, but does not interact with the natural IL-2 or IL-2R counterparts, thereby enabling selective stimulation of target cells in vivo. Here, we introduced this orthogonal IL-2R into Tregs. Upon adoptive transfer in a murine mixed hematopoietic chimerism model, orthogonal IL-2 injection significantly promoted orthogonal IL-2R+Foxp3GFP+CD4+ cell proliferation without increasing other T cell subsets, and facilitated donor hematopoietic cell engraftment followed by acceptance of heart allografts. Our data indicate that selective IL-2 stimulation enabled by cytokine receptor engineering improves Treg potential for the induction of organ transplantation tolerance.