It is now widely accepted that tumors actively devise subversion over a variety of immune players (Zitvogel et al., 2006). Counterbalancing such immune escape has become a major goal of immunotherapy today. The self nature of several tumorassociated antigens explains their weak immunogenicity and the need to overcome self-tolerance to properly activate a response against them. Immunosuppression accompanying tumor progression renders such response very unlikely. Regulatory T cells (Treg) act on maintaining tolerance and exerting immunosuppression, depending on their relative number in the CD4+ T-cells pool. The unique feature of regulatory T lymphocytes is represented by the ability to actively suppress immune responses. The characterization of minor features resulted in the classification of Treg into two main subsets: the naturally arising Treg that develop in the thymus due to high-affinity TCR triggering and suppress bystander T-cell proliferation by a still unknown mechanism requiring cell-to-cell interaction and the adaptive Treg, which develop peripherally following antigenic stimulation in the presence of IL-10 (Tr1 subset) or TGF- (Th3 subset). Such classification is susceptible to adjustments, since regulatory lymphocytes phenotypically indistinguishable from natural Treg can develop in the periphery following low-dose antigen and TGF- administration (Kretschmer et al., 2005; Wing, 2006). Therefore, thymic development, suboptimal antigenic stimulation and peripheral conversion all contribute to create the total pool of Treg, whose maintenance involves MHC II molecules (Gavin et al., 2002), the cytokine IL-2 (Malek and Bayer, 2004) and costimulatory molecules such as CD28 (Tang et al., 2003) and CD40 (Guiducci et al., 2005). In spite of their heterogeneous origin, Treg subtypes share distinctive markers. Sakaguchis group (Sakaguchi et al., 1995) first associated the regulatory phenotype to CD25, the -chain of the high-affinity receptor for interleukin 2 (IL-2). Treg depletion by means of CD25 targeting was significantly used to demonstrate their role as a common basis among the several aspects of immune regulation (Shimizu et al., 1999). Due to the intrinsic limit of this marker, associated to both activated effectors and regulatory T cells, other molecules have been proposed to identify Treg, such as the glucocorticoid-induced tumor necrosis factor receptor (GITR), OX40, the cytotoxic T-lymphocyte antigen 4 (CTLA-4), whose expression, however, only partially overlapswith the regulatory phenotype. The actual breakthrough in Treg characterization was the discovery that the forkhead box transcription factor Foxp3 was the master gene of Treg lineage (Fontenot et al., 2003; Hori et al., 2003). Very recent molecular studies have provided the renewed interpretation of Foxp3 as a mediator that amplifies and fixes pre-established molecular features of Treg cells (Gavin et al., 2007). Still, Foxp3 can be transiently expressed also by activated T cells in humans (Wang et al., 2007) and the very last identified unique signature distinguishing Treg is the downregulation of cyclic nucleotide phosphodiesterase 3B (Gavin et al., 2007). Although the molecular signature of Treg has been extensively dissected, the fine mechanisms by which they exert suppression are not fully resolved yet. The original finding that cell-to-cell contact is required for in vitro suppression (Takahashi et al., 1998; Thornton and Shevach, 1998) has been challenged by several observations in complex systems, in which both cellular interactions and soluble factors have been demonstrated to participate in overall Treg-mediated suppression. The identification of possible targets of Treg suppression has been likewise submitted to continuous update, since it has been shown that not only T cells, but also B lymphocytes, NK cells and dendritic cells are susceptible to Treg inhibition. Overall, emerging evidences place Treg central to the immunoregulatory network (Fig. 1).
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