CD4+CD25+ regulatory T cells can mediate suppressor function in the absence of transforming growth factor β1 production and responsiveness

Abstract

CD4+CD25+ regulatory T cells inhibit organ-specific autoimmune diseases induced by CD4+CD25- T cells and are potent suppressors of T cell activation in vitro. Their mechanism of suppression remains unknown, but most in vitro studies suggest that it is cell contact-dependent and cytokine independent. The role of TGF-β1 in CD4+CD25+ suppressor function remains unclear. While most studies have failed to reverse suppression with anti-transforming growth factor (TGF)-β1 in vitro, one recent study has reported that CD4+CD25+ T cells express cell surface TGF-β1 and that suppression can be completely abrogated by high concentrations of anti-TGF-β suggesting that cell-associated TGF-β1 was the primary effector of CD4+CD25+-mediated suppression. Here, we have reevaluated the role of TGF-β1 in CD4+CD25+-mediated suppression. Neutralization of TGF-β1 with either monoclonal antibody (mAb) or soluble TGF-βRII-Fc did not reverse in vitro suppression mediated by resting or activated CD4+CD25+ T cells. Responder T cells from Smad3-/- or dominant-negative TGF-β type RII transgenic (DNRIITg) mice, that are both unresponsive to TGF-β1-induced growth arrest, were as susceptible to CD4+CD25+-mediated suppression as T cells from wildtype mice. Furthermore, CD4+CD25+ T cells from neonatal TGF-β1-/- mice were as suppressive as CD4+CD25+ from TGF-β1+/+ mice. Collectively, these results demonstrate that CD4+CD25+ suppressor function can occur independently of TGF-β1.