The diversity of modulatory activities that TGFβ exerts on the immune cell functions is quite extensive and includes effects such as inhibition of effector T-cell proliferation and function, generation of regulatory T cells from naïve T lymphocytes, attenuation of cytokine production and cytolytic activity of NK cells, suppression of B cells, dendritic cells and macrophages[105]. As TGFβ kinase inhibitors is constitutively produced by MSCs and most of its effects on immune cells mentioned above have also been demonstrated to

be intrinsic features to MSCs, it is reasonable to assume the putative involvement of TGFβ as a mediator of their broad immunoregulatory properties. It has been reported that MSCs isolated from human bone marrow were able to suppress CD4+ and CD8+ T-cell proliferation induced by cellular or nonspecific mitogenic stimuli and that this effect could be reversed by the addition of monoclonal anti-TGFβ1 neutralizing antibodies[35]. Later, it was shown that human bone marrow-derived MSCs, activated by blood CD14+ monocytes, secreted TGFβ1 which is responsible for inhibition of T-lymphocyte responses[106]. It has also been observed that TGFβ1 was involved in a cell contact-dependent inhibition of T-cell proliferation by MSCs[107]. Furthermore, MSCs obtained from dental pulp were found to produce TGFβ and to suppress the proliferation

of PBMCs, which could be neutralized with anti-TGFβ antibodies[108]. In contrast, the addition of TLR-3 agonist augmented the suppressive potential of dental pulp-derived MSCs and potentiated TGFβ secretions by these cells[108]. Numerous mechanisms have been suggested to be involved in TGFβ-mediated inhibition of T-cell proliferation, differentiation and effector functions. One pathway by which TGFβ exerts its anti-proliferative effect on T lymphocytes is through blockade of the production of the T-cell mitogenic

cytokine IL-2[109]. Functional analysis revealed that this is most likely due to impaired IL-2 gene transcription as a result of inhibition of IL-2 promoter/enhancer activity[109]. In another study[110], the transcription Anacetrapib factor Smad3 was also shown to be critical for TGFβ1-mediated inhibition of IL-2 expression. Moreover, it has been demonstrated that the addition of exogenous IL-2 partially but not completely reversed the antiproliferative effects of TGFβ, indicating the suppressive activity of TGFβ on both production and intracellular signaling of IL-2[111]. TGFβ also inhibits cell proliferation through controlling the expression of cell cycle regulators, including up-regulation of cyclin-dependent kinase inhibitors (CKIs) p15, p21 and p27 and down-regulation of cell cycle-promoting factors, such as c-myc, cyclin D2 and cyclin E[112-115].