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

• DOI: 10.1084/jem.20020590
• Publication Date: 2002-07-28T22:32:53Z
• Authors: Ciriaco A. Piccir...; John J. Letterio; Angela M. Thornton; Rebecca S. McHugh; Mizuko Mamura; Hidekazu Mizuhara; Ethan M. Shevach
• Keywords: Mice, Knockout; 0301 basic medicine; Mice, Inbred BALB C; Receptor, Transforming Growth Factor-beta Type II; Antibodies, Monoclonal; Mice, Transgenic; Receptors, Interleukin-2; In Vitro Techniques; Protein Serine-Threonine Kinases; Lymphocyte Activation; T-Lymphocytes, Regulatory; Article; 3. Good health; DNA-Binding Proteins; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Animals, Newborn; Neutralization Tests; Immune Tolerance; Animals; Female; Smad3 Protein; Receptors, Transforming Growth Factor beta

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 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.