Regulatory T cells in transplantation: natural or induced?

Avoidance of inappropriate immune responses to, for example, self-antigens demands that the default mode of the adaptive immune system is necessarily one of tolerance rather than activation. But maintaining immunologic tolerance is not a simple matter. Self-tolerance is dependent primarily on clonal deletion of immature T and B cells that have high affinity and avidity for self-antigens, and for other antigens that happen to be present during this selection process. Because this system is not foolproof and self-reactive mature lymphocytes survive to populate peripheral lymphoid tissues, additional mechanisms are required for controlling the expansion of self-reactive lymphocytes in the periphery. The existence of regulatory T cells (Tr) has now gained wide acceptance. This may be partly attributable to a familiarity with the concept of the once popular T-suppressor cells that have now successfully reinvented themselves. It is also acknowledged that Tr cells represent an appropriate focus in the design of strategies aimed at inducing operational tolerance in autoimmune disease and allotransplantation. The renewed interest in T-cell suppression over the past several years stems from important complementary observations: that the development of a number of different and apparently spontaneous autoimmune diseases in animal models could be ascribed to the absence of subpopulations of T cells, and that restoration of the T-cell subpopulation rescued recipient animals from the probability of developing autoimmune disease (1– 4). Two recurring observations that have emerged from recent studies seem to define phenotypic and functional characteristics of Tr cells. First, a major population of Tr cells can be identified through their expression of CD4 and CD25. (CD25 is the chain of the trimolecular interleukin [IL]-2 receptor complex and has been conventionally described as an activation marker because it is up-regulated on activated T lymphocytes of both CD4 and CD8 subsets; it is expressed by only a small proportion of naı̈ve cells.) This holds true for both in vitro and in vivo human and rodent studies, but there is, however, a wealth of experimental evidence for the existence of other phenotypically distinct populations of Tr cells. The second important characteristic of Tr cells is that they can be naturally occurring, as in those CD4 CD25 T cells that regulate the development of autoimmune disease, or they may be induced as in transplantation studies in which recipient animals are pretreated with donor major histocompatibility complex (MHC) antigen together with immunosuppression or suboptimal costimulation, thereby preventing allograft rejection (5, 6). Natural Tr cells are selected, by as yet unknown mechanisms, in the thymus, whereas antigen-induced T regulation arises in the periphery. In the case of both clinical and experimental liver transplantation, spontaneous allograft acceptance without exogenous immunosuppression occurs frequently enough to invoke specific suppressor mechanisms. Among those proposed is suppression through natural Tr cells. The existence of Tr cells in the rat has been demonstrated by adoptive transfer studies in which T lymphocytes from Dark Agouti strain spontaneous acceptors of full MHC-disparate Lewis liver allografts were able to prevent the normally rapid rejection of Lewis hearts in Dark Agouti recipients. It is difficult to argue, from an evolutionary perspective, the need for naturally occurring T cells that regulate responses to foreign MHC. Until the molecular basis of T-cell recognition was established in the late 1980s, it was equally difficult to understand why directly alloreactive T cells exist in naı̈ve individuals in the first place (7). We now know that because T-cell receptor (TCR) gene rearrangement has evolved to select for recognition of MHC plus peptide complexes, there are situations in which strong T-cell recognition of the peptide in a complex overrules a low affinity recognition of allo-MHC in the same complex, thereby permitting direct allorecognition and avoiding the strict rules of self-MHC restriction. In addition, T-cell alloactivation may result from low-affinity but high-avidity TCR interaction with allo-MHC-peptide complexes expressed at high frequency on target cells, which have a cross-linking effect on the TCR (8). Given the fortuitous nature of direct T-cell alloreactivity, it is hard to see why or how natural Tr cells with allospecificity should arise except in the seemingly unlikely scenario of a dual production system that creates a Tr cell for every positively selected T cell (and incompletely deleted T cell) released from the thymus. Better, then, to argue that the so-called natural Tr cells that apparently prevent liver allograft rejection are, instead, Tr cells induced by the presence of the allograft, although induced Department of Surgery, School of Clinical Medicine, University of Cambridge, United Kingdom. Address correspondence to: Eleanor M Bolton, Ph.D., University Department of Surgery, Box 202, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK. E-mail: emb34@cam.ac. uk. Received 12 November 2004. Accepted 16 November 2004. Copyright © 2005 by Lippincott Williams & Wilkins ISSN 0041-1337/05/7906-643 DOI: 10.1097/01.TP. 0000155178.20481. 77