There may be other possible factors that promote the proliferation of DN Treg cells in combination with IL-15, possibly other cytokines or co-stimulatory molecules that deliver signals to DN Treg cells. This is the subject of ongoing investigations. The function of Treg cells has been described, Wnt activity both in vitro and in vivo. It has been proposed that Treg cells function as modulators of autoimmune responses because of their suppressive effect on autoreactive lymphocytes. Furthermore, this suppressive function can be transferred by injecting

Treg cells into autoimmune animal model systems.7 The Treg cells have also been shown to function in many non-autoimmune models such as graft-versus-host disease and allergy.48–51 In contrast, Treg cells can interrupt the activation of effector T cells responding to tumour cells and infectious pathogens.46 However, clinical applications using Treg cell suppressive function have been limited Ibrutinib clinical trial because of the hypoproliferative property and polyclonal nature of Treg cells. In vitro studies using cTreg cells show that only a relatively high ratio of Treg : effector cells can suppress the effector cells (i.e. 5 : 1 to 1 : 1). As a result

of this inefficient in vitro suppression, the therapeutic potential of Treg cells has been critically limited. However, HBeAg-specific DN Treg cells demonstrate superior suppressive effects on effector cells at effector cell : Treg click here cell ratios as low as 32 : 1 (see Fig. 5). The multiple mechanisms of suppression used by Treg cells is an ongoing subject of research and remains somewhat controversial. The suppressive effects of cTreg cells in vitro have been reported mostly on CD4+ and CD8+ effector cells, but have also been found to act directly on APCs and natural killer cells.52–56 Inhibitory cytokines, IL-10 and transforming growth factor(TGF)-β are

known to be produced by cTreg cells and thought to be a part of the mechanism of Treg cells.57,58 According to our preliminary data in a transwell system, IL-10 and TGF-β are not candidates as the primary mediators of suppression demonstrated by HBeAg-specific DN Treg cells (data not shown). Another report showed that the regulatory function of Treg cells is serine protease granzyme-B (GZ-B)-dependent using GZ-B−/− mice.59 Other suppressive mechanisms have been suggested to function via cell–cell contact. CTLA-4, FAS–FASL, GITR and CD103 have also been suggested to play a role in the function of Treg cells. Recently, the inhibitory function of Treg cells has been demonstrated to be mediated through the exoenzymes CD73/CD39.60–62 Interestingly, a high frequency of HBeAg-specific DN Treg cells are CD73+/CD39+ after activation (Fig. 11). We are investigating whether this pathway may explain the efficient immunoregulation mediated by HBeAg-specific DN Treg cells.