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Rapid Suppression of Cytokine Transcription in Human CD4⁺CD25^– T Cells by CD4⁺Foxp3⁺ Regulatory T Cells: Independence of IL-2 Consumption, TGF-, and Various Inhibitors of TCR Signaling¹

Nina Oberle^2,*, Nadine Eberhardt^*, Christine S. Falk, Peter H. Krammer^* and Elisabeth Suri-Payer^*

^* Division of Immunogenetics, Tumorimmunology Program, German Cancer Research Center, Heidelberg, Germany; and Immunomonitoring Unit, National Center for Tumor Diseases and Institute for Immunology, Heidelberg, Germany

CD4⁺CD25^high forkhead box P3⁺ regulatory T cells (Treg) are critical mediators of peripheral self-tolerance and immune homeostasis. Treg suppress proliferation and cytokine production of conventional T cells (Tcon). The exact mechanism of suppression, however, is still unknown. To gain a better understanding of Treg function, we investigated the kinetics of cytokine suppression in Tcon reisolated from cocultures with preactivated human Treg. Treg inhibited induction of Th1 cytokine mRNA as early as 1 h after stimulation, whereas induction/suppression of Th2 cytokines was delayed to 10–15 h. We show that immediate cytokine mRNA suppression in Tcon was neither dependent on TGF-/IL-10 or IL-2 consumption, nor on induction of the transcriptional-repressor forkhead box P3 or other anergy-related genes (e.g., gene related to anergy, transducer of ErbB-2, forkhead homolog-4, repressor of GATA, inducible cAMP early repressor). In contrast, lymphocyte activation gene 3, suppressor of cytokine signaling 1, and suppressor of cytokine signaling 3 mRNA were strongly up-regulated in Tcon in the presence of Treg. However, protein analysis did not confirm a role for these proteins in early suppression. Thus, the identification of a fast inhibitory mechanism in Tcon induced by Treg constitutes an important step for future efforts to unravel the entire elusive suppressive mechanism.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from the "Landesstiftung Baden-Württemberg" Germany (P-LS-AL/13) to E.S.-P. and SFB 405 to P.H.K.

² Address correspondence and reprint requests to Dr. Nina Oberle, Division of Immunogenetics (D030), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg. E-mail address: N.Oberle{at}dkfz.de

³ Abbreviations used in this paper: FOXP3, forkhead box P3; FOXJ1, forkhead homolog-4; GRAIL, gene related to anergy; ICER, inducible cAMP early repressor; LAG-3, lymphocyte activation gene 3; LKLF, lung Krüppel-like factor; rh, recombinant human; ROG, repressor of GATA; SOCS, suppressor of cytokine signaling; Tcon, conventional T cell; TOB, transducer of ErbB-2; Treg, regulatory T cell.