Seminars in Immunology 16 (2004) 119–126 Regulatory T cells and organ transplantation Herman Waldmann ∗ , Luis Graca, Stephen Cobbold, Elizabeth Adams, Masahide Tone,Yuki Tone Sir William Dunn School of Pathology, South Parks Road, Oxford OX13RE, UK Abstract Empirical studies attempting to explain tolerance to transplanted tissues have demonstrated a regulatory role for CD4+ T-cells. We here propose that regulatory T-cells mediating transplantion tolerance comprise two sets which can functionally complement each other. The CD4+CD25+ “natural regulator” arises in the thymus, and is preoccupied with self-antigens expressed at sites of inflammation. The second, comprising both CD4+CD25+ (FoxP3+) and CD4+CD25- Tr1-like cells are induced by persistent danger-free antigen in the periphery. The role of these cells is to moderate immune responses to prevent tissue destruction while allowing microbial elimination. © 2004 Elsevier Ltd. All rights reserved. Keywords: Tolerance; Transplantation; Regulation; Privilege 1. Introduction A major goal in organ transplantation is to be able to har- ness tolerance processes so as to minimize the need for im- munosuppressive drugs. Studies in the mouse have shown that this can be achieved through two distinct strategies. Deletional mechanisms can be effectively invoked through the creation of mixed hemopoietic chimerism [1–3], while regulatory mechanisms can be invoked through recruitment of specialised CD4+ T cells that can prevent graft rejec- tion [4] These same regulatory T cells show specificity for donor antigens processed by host antigen-presenting cells (APC) [5], and are indeed dependent on continuous antigen exposure to stay active [6–8]. They are also responsible for extending suppression by linked-suppression to additional antigens expressed within tolerated tissue [9], and for the spreading of dominant tolerance to further cohorts of naive T cells as they develop, through a process we have coined infectious tolerance [4]. Insofar as the creation of mixed chimerism may prove to be operationally difficult to achieve as a routine proce- dure, there is substantial interest in the seemingly potent ∗ Corresponding author. Tel.: +44-1865-275503; fax: +44-1865-275501. E-mail addresses: herman.waldmann@path.ox.ac.uk (H. Waldmann), luis.graca@path.ox.ac.uk (L. Graca), stephen.cobbold@path.ox.ac.uk (S. Cobbold), elizabeth.adams@path.ox.ac.uk (E. Adams), mtone@molbiol.ox.ac.uk (M. Tone), ytone@molbiol.ox.ac.uk (Y. Tone). anti-rejection potential of allo-antigen-specific regulatory T cells. Although empiricism led to their discovery, there is a need to establish some basic properties of these cells. We need to know whether they represent a preformed thymic lineage or whether they are induced to regulate by appropri- ate exposure to antigen. If the former, are these cells iden- tical to “natural” CD4+CD25+ T cells known to regulate autoimmune disease and gut immunopathology? If the lat- ter, can we establish the rules by which one can induce their development in a therapeutically relevant way? This is a very speculative and, hopefully, provocative ar- ticle attempting to make sense of a patchwork of incomplete data in the field. Its underlying theme is that regulatory T cells interact with the tissues they serve to promote the cre- ation of transient but privileged microenvironments. Nor- mally they prevent autoimmunity, and also immunopathol- ogy from exaggerated responses to microbes. Therapeuti- cally, they may have potential to turn off unwanted re- sponses, were we able to exploit their capacity to establish protective microenvironments in tissues. For sake of clarity the following discussion will use the terminology T regtrans as the abbreviation for T cells that me- diate dominant transplantation tolerance, and T reg as the ab- breviation for any regulatory T cell. 2. Natural regulatory T cells There is now good evidence for a thymic lineage of T cells with regulatory function [10,11]. These T cells 1044-5323/$ – see front matter © 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.smim.2003.12.007