Large-scale depletion of CD25+ regulatory T cells from patient leukapheresis samples.

Naturally occurring CD4+ CD25+ T regulatory (Treg) cells are involved in the maintenance of homeostatic peripheral self tolerance by suppressing autoreactive T cells.1 In mice and humans, Treg cells develop in the thymus and represent about 5% to 10% of the peripheral CD4+ T-cell compartment. These regulatory cells are characterized by their constitutive expression of CD25, CTLA-4, glucocorticoid-induced TNFR (GITR), and the transcription factor Forkhead box P3 (Foxp3).1 Compared with CD25−CD4+ T cells, Treg cells exhibit a hypoproliferative capacity and possess the ability to suppress CD8+ and CD25− CD4+ T cell activation in vitro. The mechanism of suppression is cell contact-dependent, but how regulatory T cells induce and maintain self tolerance is unknown. The importance of Treg cells as key mediators of self tolerance is witnessed in individuals genetically predisposed to the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), a recessive and often fatal disorder of early childhood caused by loss of function mutations of FOXP3 and the resultant lack of Treg cells.2 In mice, the scurfy strain harbor a similar mutation in Foxp3 resulting in the absence of Treg cells and consequentially the induction of fatal T cell–mediated autoimmunity mediated by unregulated CD4+ T-helper cells directed against self tissue antigens.3 Like scurfy mice, the depletion of Treg cells4 from normal mice results in autoimmune destruction of a number of self tissue organs. Further, transfer of a normal repertoire of CD25− CD4+ T-helper cells to lymphopenic mice results in autoimmune induction, a process inhibited by the co-transfer of Treg cells. 3 In the absence of CD25+ Treg cells, organ-specific destruction of tissue expressing a self antigen can be augmented with self antigen vaccination or through the provision of inflammatory signals.5 Furthermore, depletion of Treg cells can enhance tumor protection to tumor-associated antigens expressed as self antigens and elicit concomitant immunity in tumor-bearing mice.6,7 The influence of CD4+ T-cell subsets on adoptive immunotherapy has recently been evaluated using a well-described murine model of cancer wherein adoptive transfer of tumor/self reactive CD8+ T cells with vaccination and IL-2 leads to regression of large established melanoma in lymphodepleted hosts.8 Although CD4+ T cells can affect CD8+ T-cell effector function, memory, and maintenance, the absence of CD4+ T cells augmented adoptive immunotherapy when using CD8+ T cells directed against a persisting tumor/self antigen.9 However, adoptive transfer of CD25−CD4+ T-helper cells with tumor/self reactive CD8+ T cells and vaccination into CD4+ T cell-deficient recipients resulted in autoimmunity and regression of established tumor. Maintenance of tumor/self CD8+ effector cells was dependent on CD25− CD4+ T helper cells capable of producing IL-2. Transfer of CD25+ Treg cells alone or combined with CD25− CD4+ T-helper cells inhibited effective immunotherapy. Peripheral blood lymphocytes from melanoma patients contain functional CD4+ CD25+ Treg cells, and melanoma antigen-specific Treg cells have been described.10,11 In addition, CD4+ CD25+ Treg cells are overrepresented in human metastatic melanoma lymph nodes and can inhibit the function of infiltrating T cells.12 In ovarian carcinoma, Treg cells are reported to contribute to the growth of human tumors in vivo by suppressing tumor-specific T-cell immunity and have been reported to be associated with a high death hazard and reduced survival.13 Thus, the negative immunoregulatory effects of Treg cells may explain the poor clinical response rates reported in cancer patients receiving non-immunodepleting immunotherapy, and offers a foundation for novel immunotherapeutic approaches designed to neutralize the suppressive effects of Treg cells in vivo and bolster antitumor immune responses.