CD4+CD25+ T Regulatory Cells in Transplantation Tolerance: 25 Years On

In the 1970s, the capacity of T cells to inhibit immunity and those from transplant tolerant hosts to transfer alloantigen-specific suppression to lymphopenic recipients was described. CD4 T suppressor cells that ex vivo reverted to effector cells were described in the 1980s. Their antigen-specific suppressor function could be preserved by stimulation by specific donor alloantigen and cytokines from activated lymphocytes. This led to the finding that alloantigen-specific T suppressor cells express IL-2 receptor (CD25) and that IL-2 in part promotes their survival.Whether these alloantigen-specific CD4CD25FOXP3 regulatory T (Treg) cells are progeny of thymic-derived CD4CD25FOXP3 Treg (tTreg) cells or are induced from peripheral effector CD4CD25FOXP3T cells (iTreg) cells is still debated.In vitro studies of antigen specific Treg has been difficult as they die in the absence of cytokines produced by immune activated cells. The antigen-specific CD4CD25 T cells that control rejection in tolerant hosts differ from the naive tTreg. Thymic-derived Treg cells are not antigen-specific, and very high ratios are required to suppress rejection. Thymic-derived Treg cells can be expanded ex vivo and are currently being tested in trials to control allograft rejection and graft versus host disease.Thymic-derived Treg cells with specific receptors for alloantigen are activated by either IL-2 or IL-4 but rapidly become dependent on other cytokines, respectively, IFN-γ or IL-12 if activated by IL-2, or IL-5 if activated by IL-4. The Th1 and Th2 pathways for activation of tTreg produce more potent antigen-specific Treg that only suppress specific donor rejection. After 25 years, much remains unknown about antigen-specific CD4CD25FOXP3 Treg-mediating transplant tolerance.