ABSTRACT
CD4(+) Foxp3(+) T regulatory cells (Tregs ) are essential for maintaining immunological tolerance, which could be harnessed for novel cell-based therapies to prevent allograft rejection and control autoimmunity. However, the use of Tregs for therapy is hindered by the inability to generate sufficient cell numbers to inhibit desired immune response(s) and achieve stable engraftment of the donor-Treg cell inoculums. The present study was undertaken to investigate the in vivo requirements to promote engraftment of adoptively transferred Tregs and induce tolerance. We established that not only is peripheral space required, but competition from endogenous Tregs must be minimized for successful donor-Treg engraftment with IL-2 critical for driving their proliferation and survival. Moreover, these studies revealed a critical level of donor-Treg engraftment was required for tolerance induction to skin transplants. These mouse studies lay the foundation for development of novel Treg approaches for tolerance induction in the clinic involving not only organ or cellular transplantation, but also to re-establish self-tolerance in autoimmune settings.