Original Article

Cell Contact–dependent Immunosuppression by CD4⁺CD25⁺ Regulatory T Cells Is Mediated by Cell Surface–bound Transforming Growth Factor ß

Correspondence to: Warren Strober, National Institutes of Health, Building 10, Rm. 11N238, 10 Center Dr., Bethesda, MD 20892. Tel:301-496-6810 Fax:301-402-2240 E-mail:wstrober{at}niaid.nih.gov.

CD4⁺CD25⁺ T cells have been identified as a population of immunoregulatory T cells, which mediate suppression of CD4⁺CD25^- T cells by cell–cell contact and not secretion of suppressor cytokines. In this study, we demonstrated that CD4⁺CD25⁺ T cells do produce high levels of transforming growth factor (TGF)-ß1 and interleukin (IL)-10 compared with CD4⁺CD25^- T cells when stimulated by plate-bound anti-CD3 and soluble anti-CD28 and/or IL-2, and secretion of TGF-ß1 (but not other cytokines), is further enhanced by costimulation via cytotoxic T lymphocyte–associated antigen (CTLA)-4. As in prior studies, we found that CD4⁺CD25⁺ T cells suppress proliferation of CD4⁺CD25^- T cells; however, we observed here that such suppression is abolished by the presence of anti–TGF-ß. In addition, we found that CD4⁺CD25⁺ T cells suppress B cell immunoglobulin production and that anti–TGF-ß again abolishes such suppression. Finally, we found that stimulated CD4⁺CD25⁺ T cells but not CD4⁺CD25^- T cells express high and persistent levels of TGF-ß1 on the cell surface. This, plus the fact that we could find no evidence that a soluble factor mediates suppression, strongly suggests that CD4⁺CD25⁺ T cells exert immunosuppression by a cell–cell interaction involving cell surface TGF-ß1.

Key Words: T lymphocytes, suppressor-effector, CD4-positive T lymphocytes, receptors, interleukin 2, transforming growth factors, autoimmune diseases

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• Dong, M., Blobe, G. C. (2006). Role of transforming growth factor-beta in hematologic malignancies. Blood 107: 4589-4596 [Abstract] [Full Text]  
• Sharabi, A., Zinger, H., Zborowsky, M., Sthoeger, Z. M., Mozes, E. (2006). A peptide based on the complementarity-determining region 1 of an autoantibody ameliorates lupus by up-regulating CD4+CD25+ cells and TGF-beta. Proc. Natl. Acad. Sci. USA 103: 8810-8815 [Abstract] [Full Text]  
• Noble, A., Giorgini, A., Leggat, J. A. (2006). Cytokine-induced IL-10-secreting CD8 T cells represent a phenotypically distinct suppressor T-cell lineage. Blood 107: 4475-4483 [Abstract] [Full Text]  
• Veldhoen, M., Moncrieffe, H., Hocking, R. J., Atkins, C. J., Stockinger, B. (2006). Modulation of Dendritic Cell Function by Naive and Regulatory CD4+ T Cells. J. Immunol. 176: 6202-6210 [Abstract] [Full Text]  
• Beyer, M., Kochanek, M., Giese, T., Endl, E., Weihrauch, M. R., Knolle, P. A., Classen, S., Schultze, J. L. (2006). In vivo peripheral expansion of naive CD4+CD25high FoxP3+ regulatory T cells in patients with multiple myeloma. Blood 107: 3940-3949 [Abstract] [Full Text]  
• Duchmann, R, Zeitz, M (2006). T regulatory cell suppression of colitis: the role of TGF-{beta}. Gut 55: 604-606 [Full Text]  
• Fantini, M C, Becker, C, Tubbe, I, Nikolaev, A, Lehr, H A, Galle, P, Neurath, M F (2006). Transforming growth factor {beta} induced FoxP3+ regulatory T cells suppress Th1 mediated experimental colitis. Gut 55: 671-680 [Abstract] [Full Text]  
• Yang, Z.-Z., Novak, A. J., Stenson, M. J., Witzig, T. E., Ansell, S. M. (2006). Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma. Blood 107: 3639-3646 [Abstract] [Full Text]  
• Barao, I., Hanash, A. M., Hallett, W., Welniak, L. A., Sun, K., Redelman, D., Blazar, B. R., Levy, R. B., Murphy, W. J. (2006). Suppression of natural killer cell-mediated bone marrow cell rejection by CD4+CD25+ regulatory T cells. Proc. Natl. Acad. Sci. USA 103: 5460-5465 [Abstract] [Full Text]  
• Zhang, X., Reddy, J., Ochi, H., Frenkel, D., Kuchroo, V. K., Weiner, H. L. (2006). Recovery from experimental allergic encephalomyelitis is TGF-{beta} dependent and associated with increases in CD4+LAP+ and CD4+CD25+ T cells. Int Immunol 18: 495-503 [Abstract] [Full Text]  
• Kashiwada, M., Cattoretti, G., McKeag, L., Rouse, T., Showalter, B. M., Al-Alem, U., Niki, M., Pandolfi, P. P., Field, E. H., Rothman, P. B. (2006). Downstream of Tyrosine Kinases-1 and Src Homology 2-Containing Inositol 5'-Phosphatase Are Required for Regulation of CD4+CD25+ T Cell Development. J. Immunol. 176: 3958-3965 [Abstract] [Full Text]  
• Chen, C., Lee, W.-h., Zhong, L., Liu, C.-P. (2006). Regulatory T Cells Can Mediate Their Function through the Stimulation of APCs to Produce Immunosuppressive Nitric Oxide. J. Immunol. 176: 3449-3460 [Abstract] [Full Text]  
• Keino, H., Takeuchi, M., Kezuka, T., Hattori, T., Usui, M., Taguchi, O., Streilein, J. W., Stein-Streilein, J. (2006). Induction of Eye-Derived Tolerance Does Not Depend on Naturally Occurring CD4+CD25+ T Regulatory Cells.. IOVS 47: 1047-1055 [Abstract] [Full Text]  
• Alvarez, D., Swirski, F. K., Yang, T.-C., Fattouh, R., Croitoru, K., Bramson, J. L., Stampfli, M. R., Jordana, M. (2006). Inhalation Tolerance Is Induced Selectively in Thoracic Lymph Nodes but Executed Pervasively at Distant Mucosal and Nonmucosal Tissues. J. Immunol. 176: 2568-2580 [Abstract] [Full Text]  
• Azevedo, M. S. P., Yuan, L., Pouly, S., Gonzales, A. M., Jeong, K. I., Nguyen, T. V., Saif, L. J. (2006). Cytokine Responses in Gnotobiotic Pigs after Infection with Virulent or Attenuated Human Rotavirus. J. Virol. 80: 372-382 [Abstract] [Full Text]  

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