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. CD4T 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 Treg are progeny of thymic derived CD4CD25FOXP3Treg (tTreg) or are induced from peripheral effector CD4CD25FOXP3T cells (iTreg) 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 CD4CD25T cells that control rejection in tolerant hosts differ from the naive tTreg. tTreg are not antigen specific and very high ratios are required to suppress rejection. tTreg can be expanded ex vivo, and are currently being tested in trials to control allograft rejection and GVHD.tTreg 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 CD4CD25FOXP3Treg mediating transplant tolerance.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.