CD4+CD25+ Regulatory T Cells Can Mediate Suppressor Function in the Absence of Transforming Growth Factor β1 Production and Responsiveness

CA Piccirillo, JJ Letterio, AM Thornton… - The Journal of …, 2002 - rupress.org
CA Piccirillo, JJ Letterio, AM Thornton, RS McHugh, M Mamura, H Mizuhara, EM Shevach
The Journal of experimental medicine, 2002rupress.org
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+ regulatory T cells inhibit organ-specific autoimmune diseases induced by CD4+CD25T 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 wild-type 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.
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