The role of peripheral T-cell deletion in transplantation tolerance

The apoptotic deletion of thymocytes that express self-reactive antigen rec eptors is the basis: of central (thymic) self-tolerance. However, it is cle ar that some autoreactive T cells escape deletion in the thymus and exist a s mature lymphocytes in the periphery. Therefore, peripheral mechanisms of tolerance are also crucial, and failure of these peripheral mechanisms lead s to autoimmunity. Clonal deletion, clonal anergy and immunoregulation and/ or suppression have been suggested as mechanisms by which 'inappropriate' T -lymphocyte responses may be controlled in the periphery. Peripheral clonal deletion, which improves the apoptotic elimination of lymphocytes, is crit ical for T-cell homeostasis during normal immune responses, and is recogniz ed as an important process by which self-tolerance is maintained. Transplan tation of foreign tissue into an adult host represents a special case of 'i nappropriate' T-cell reactivity that is subject to the same central and per ipheral tolerance mechanisms that control reactivity against self. In this case, the unusually high frequency of naive T cells able to recognize and r espond against non-self-allogeneic major historumpatility complex (MHC) ant igens leads to an exceptionally large pool of pathogenic effector lymphocyt es that must be controlled if graft rejection is to be avoided. A great dea l of effort has been directed towards understanding the role of clonal aner gy and/or active immunoregulation in the induction of peripheral transplant ation tolerance but, until recently; relatively little progress had been ma de towards defining the potential contribution of clonal deletion. Here, we outline recent data that define a clear requirement for deletion in the in duction of peripheral transplantation tolerance across MHC barriers, and di scuss the potential implications of these results in the context of current treatment modalities used in the clinical transplantation setting.