Regulatory T-Cell Therapy in the Induction of Transplant Tolerance: The Issue of Subpopulations

Clinical tolerance induction to permit minimization or cessation of immunosuppressive drugs is one of the key research goals in solid organ transplantation. The use of ex vivo expanded or manipulated immunologic cells, including CD(4+)CD25(hi)FOXP3(+) regulatory T cells (Tregs), to achieve this aim is already a reality, with several trials currently recruiting patients. Tregs are a highly suppressive, nonredundant, population of regulatory cells that prevent the development of autoimmune diseases in mammals. Data from transplanted humans and animal models support the notion that Tregs can mediate both induction and adoptive transfer of transplantation tolerance. However, human Tregs are highly heterogeneous and include subpopulations with the potential to produce the proinflammatory cytokine interleukin-17, which has been linked to transplant rejection. Tregs are also small in number in the peripheral circulation, thus they require ex vivo expansion before infusion into man. Selection of the most appropriate Treg population for cell therapy is, therefore, a critical step in ensuring successful clinical outcomes. In this review, we discuss Treg subpopulations, their subdivision based on nonmutually exclusive criteria of origin, expression of immunologic markers and function, availability in the peripheral blood of patients awaiting transplantation, and their suitability for programs of cell-based therapy.