0041-1337/04/7701-S6/0 TRANSPLANTATION Vol. 77, S6–S8, No. 1, January 15, 2004 Copyright © 2004 by Lippincott Williams & Wilkins, Inc. Supplement REGULATORY T CELLS: POTENTIAL IN ORGAN TRANSPLANTATION 1 KATHRYN J. WOOD, 2,3 SHIQIAO LUO, 2 AND AHMED AKL 2 Active regulation or suppression of donor reactive cells is emerging as a key mechanism for inducing and maintaining unresponsiveness to donor alloantigens. Accumulating evidence suggests that a balance be- tween immunoregulation and deletion of donor al- loantigen reactive T cells can provide effective control of immune responsiveness after organ or cell trans- plantation. In many settings, immunoregulatory activ- ity is enriched in CD4  T cells that express high levels of CD25, and common mechanisms appear to be re- sponsible for the activity of regulatory T cells in both transplantation and the control of reactivity to self-antigens. Immunoregulation operates at the level of the innate and the adaptive immune systems, and integration of these mechanisms is critical for the overall control of immune responsiveness (1–4). Lymphocyte populations capable of suppressing antigen-specific immune responses were identi- fied more than 30 years ago (5, 6). At that time, the cellular and molecular characteristics of these so-called suppressor cells were not clearly defined, but recently, a number of important findings have suggested that the identification and characterization of such regulatory T cells (Treg) is possible. IDENTIFICATION of TREG The identification and quantitation of alloantigen-specific regulatory cell populations could be a useful tool for assess- ing the induction of unresponsiveness to donor alloantigens after transplantation. Expression of CD25, the -subunit of the interleukin (IL)-2 receptor, by CD4 + T cells has to date been the most useful way of enriching for cells with regula- tory activity (7, 8). Recipient-derived CD25 + CD4 + T cells have been shown to have potent regulatory properties in both the induction and maintenance phases of tolerance to alloan- tigens in vivo in mice (9 –14). In bone marrow transplanta- tion, donor-derived CD25 + CD4 + T cells have also been shown to protect against graft-versus-host disease (2–4). A human equivalent of mouse CD25 + CD4 + Treg is present in human peripheral blood and thymus (15–20). Although CD25 is a useful way of identifying Treg within a mixture, it is clearly not a marker that is exclusive to Treg; moreover, it may be unstable. Other phenotypic or molecular markers are therefore required. Studies designed to find molecular markers that are specific for Treg are in progress in both experimental and human systems, and the list of candidate markers is growing. At present, the list includes CD45RB, cytotoxic T-lymphocyte–associated antigen (CTLA)-4, glucocorticoid-induced tumor necrosis factor re- ceptor family-related gene (GITR or TNFRSF18), CD122, CD103, and the transcription factor Foxp3 (21). No one mol- ecule or gene has yet been found that fulfills the criteria of exclusivity and stability and, so far, it is probably easier to rule out rather than rule in molecules whose expression is exclusively associated with Treg. Nevertheless, it is possible to use these molecules to enrich for T cells with regulatory activity, an important step toward developing their potential. PROPERTIES OF TREG Alloantigen Recognition. Alloantigens can be recognized as intact major histocompatibility complex (MHC) molecules presented by donor-derived antigen-presenting cells (APC), the so-called direct pathway of allorecognition, or after pro- cessing of either MHC or minor histocompatibility antigens to produce allopeptides that can be presented by recipient MHC molecules expressed by recipient APC (22). This second pathway is usually referred to as the indirect pathway of allorecognition, and evidence is emerging that indirect al- lorecognition may be the dominant pathway used by CD25 + CD4 + Treg (11, 23). Control of Effector T Cells. In vivo, Treg have been shown to be capable of preventing rejection initiated by CD4 + cells in both organ (11, 12) and bone marrow transplantation (2–4). CD25 + CD4 + T cells generated as a result of co-stim- ulation blockade at the time of transplantation have also been shown to be capable of suppressing rejection initiated by a 100-fold excess over the minimum number of donor alloan- tigen-specific CD8 + T-cell receptor transgenic T cells re- quired to trigger rejection, clearly demonstrating the potency of CD25 + CD4 + T cells once in place (24). Treg can also impact the functional activity of other T cells and APC (25), resulting in inhibition of cytokine production and secretion; decrease of co-stimulatory molecule expression, adhesion molecule expression, or both; inhibition of proliferation; in- duction of anergy or, in some circumstances, elimination of the affected population by promoting cell death; or even conversion to a regulatory phenotype in the so-called process of infectious tolerance (26, 27). Role of Cytokines. There appears to be little correlation between the role that cytokines play in the activity of Treg in vivo and in vitro. In vivo experiments have been clear in demonstrating a role for cytokines in regulatory cell function in transplant models. IL-10 blockade abrogated suppression 1 K.J.W. holds a Royal Society Wolfson Research Merit Award. Work in K.J.W.’s laboratory is funded by The Wellcome Trust, Eu- ropean Union, National Kidney Research Fund, and Roche Organ Transplant Research Foundation. S.L. is a China Scholarship Coun- cil Research Fellow. A.A. is an International Society of Nephrology Research Fellow. 2 Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom. 3 Address correspondence to: Kathryn J. Wood, Professor of Im- munology, Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United King- dom. E-mail: kathryn.wood@nds.ox.ac.uk. S6 DOI: 10.1097/01.TP.0000106477.70852.29