Thymus-derived T reg cell (tT reg cell)' should be used instead of 'natural T reg cell (nT reg cell)'. 2. 'Peripherally derived T reg cell (pT reg cell)' should be used instead of 'induced or adaptive T reg cell (iT reg cell or aT reg cell)'. 3. 'In vitro-induced T reg cell (iT reg cell)' should be used to clearly distinguish between those T reg cell populations generated in vivo versus those generated in vitro. 4. T reg cell terms should be used only when there is definitive evidence justifying their use. 5. The development and use of new T reg cell terminology should be limited, especially for subpopulations.

IntroductionTransplantation of cells and organs is regarded as the only therapeutic choice for end-stage failure of several organs and has been made possible by the development of powerful immunosuppressive treatments that prevent transplant rejection. However, most of these drugs nonspecifically target the immune response, leading to unwanted side effects, and have limited ability to prevent chronic rejection. 1,2 The ultimate goal in transplantation is, therefore, the induction of a sustained state of specific tolerance to donor alloantigens with minimization or complete withdrawal of immunosuppression. Many studies in rodents have shown that it is possible to exploit the mechanisms that normally maintain immune homeostasis and tolerance to self-antigens to induce tolerance to alloantigens. 3 Immunologic tolerance involves central and peripheral mechanisms. Central tolerance results from intrathymic deletion of T cells with high avidity for thymically expressed antigens. Peripheral tolerance can be achieved by various mechanisms including deletion of activated/effector T cells, anergy induction, and active regulation of effector T cells. 4,5 CD4 ϩ T cells with regulatory function have been shown to play a critical role in the maintenance of transplantation tolerance. 6 The CD25 ϩ fraction of CD4 ϩ T cells mediates tolerance on adoptive transfer into a naive host. 7-9 CD4 ϩ CD25 ϩ regulatory T (Treg) cells are a naturally occurring population of CD4 ϩ T cells that constitutively express the IL-2 receptor ␣-chain (CD25). 10 These cells were shown to be potent suppressors of activated T cells in vitro 11,12 and to be crucial for the control of autoreactive T cells 13 and of the effector function of alloreactive CD4 ϩ and CD8 ϩ T cells in transplantation models in vivo. 8,14 The precise mechanisms by which these Treg cells exert their suppressive function remain to be defined. Surface molecules such as cytotoxic T lymphocyteassociated antigen 4 (CTLA-4), 15,16 the glucocorticoid-induced tumor necrosis factor receptor (GITR), 17 and cytokines such as TGF-␤ 18-20 and IL-10 8,21 are thought to play roles in different animal models.Several studies have implied that the regulation mediated by Treg cells is dependent on a continuous supply of alloantigens 8,[22][23][24] or tissue-specific target autoantigens, 25,26 suggesting that these cells have specificity for alloantigens or autoantigens. In transplantation, alloreactive CD4 ϩ T cells with indirect allospecificity are thought to play a key role in chronic rejection, and the control of these pathogenic effector cells by donor-specific Treg cells could, therefore, result in transplantation tolerance. [27][28][29][30][31] However, the possibility of using Treg cells as immunotherapy for the induction of antigen-specific tolerance is limited by cell number. Indeed, the entire pool of Treg cells accounts for only 5% to 10% of CD4 ϩ T cells in the peripheral blood of healthy persons. 10,32,33 In this study, we have explored whether in vivo alloresponses could be regulated...

T cell responses to MHC-mismatched transplants can be mediated via direct recognition of allogeneic MHC