The Journal of Experimental Medicine
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Published 15 July 2002. doi:10.1084/jem.20020590
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© Rockefeller University Press, 0022-1007/2002/7/237/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 2, July 15, 2002 237-246

CD4+CD25+ Regulatory T Cells Can Mediate Suppressor Function in the Absence of Transforming Growth Factor ß1 Production and Responsiveness

Ciriaco A. Piccirillo1, John J. Letterio2, Angela M. Thornton1, Rebecca S. McHugh1, Mizuko Mamura2, Hidekazu Mizuhara1 and Ethan M. Shevach1

1 Laboratory of Immunology, National Institute of Allergy and Infectious Diseases
2 Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

Address correspondence to Ethan M. Shevach, Laboratory of Immunology, NIAID, NIH, Bldg. 10, Rm. 11N315, 10 Center Dr., Bethesda, MD 20892-1892. Phone: 301-496-6449; Fax: 301-496-0222; E-mail: EShevach{at}niaid.nih.gov

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-ß1 in CD4+CD25+ suppressor function remains unclear. While most studies have failed to reverse suppression with anti–transforming growth factor (TGF)-ß1 in vitro, one recent study has reported that CD4+CD25+ T cells express cell surface TGF-ß1 and that suppression can be completely abrogated by high concentrations of anti–TGF-ß suggesting that cell-associated TGF-ß1 was the primary effector of CD4+CD25+-mediated suppression. Here, we have reevaluated the role of TGF-ß1 in CD4+CD25+-mediated suppression. Neutralization of TGF-ß1 with either monoclonal antibody (mAb) or soluble TGF-ßRII-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-ß type RII transgenic (DNRIITg) mice, that are both unresponsive to TGF-ß1–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-ß1-/- mice were as suppressive as CD4+CD25+ from TGF-ß1+/+ mice. Collectively, these results demonstrate that CD4+CD25+ suppressor function can occur independently of TGF-ß1.

Key Words: CD4+ suppressor T cells • autoimmunity • tolerance • immunoregulation • IL-2 receptor


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