HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Classen, S. Articles by Schultze, J. L. Search for Related Content PubMed PubMed Citation Articles by Classen, S. Articles by Schultze, J. L.

Human Resting CD4⁺ T Cells Are Constitutively Inhibited by TGF under Steady-State Conditions^1,2

Sabine Classen^3,*, Thomas Zander^3,*, Daniela Eggle^*, Jens M. Chemnitz^*, Benedikt Brors, Ingrid Büchmann^*, Alexey Popov^*, Marc Beyer^*, Roland Eils, Svenja Debey^* and Joachim L. Schultze^4,*

^* Department of Internal Medicine I, Molecular Tumor Biology and Tumor Immunology, University of Cologne, Cologne, Germany; and Division for Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany

Based on studies in knockout mice, several inhibitory factors such as TGF, IL-10, or CTLA-4 have been implicated as gate keepers of adaptive immune responses. Lack of these inhibitory molecules leads to massive inflammatory responses mainly mediated by activated T cells. In humans, the integration of these inhibitory signals for keeping T cells at a resting state is less well understood. To elucidate this regulatory network, we assessed early genome-wide transcriptional changes during serum deprivation in human mature CD4⁺ T cells. The most striking observation was a "TGF loss signature" defined by down-regulation of many known TGF target genes. Moreover, numerous novel TGF target genes were identified that are under the suppressive control of TGF. Expression of these genes was up-regulated once TGF signaling was lost during serum deprivation and again suppressed upon TGF reconstitution. Constitutive TGF signaling was corroborated by demonstrating phosphorylated SMAD2/3 in resting human CD4⁺ T cells in situ, which were dephosphorylated during serum deprivation and rephosphorylated by minute amounts of TGF. Loss of TGF signaling was particularly important for T cell proliferation induced by low-level TCR and costimulatory signals. We suggest TGF to be the most prominent factor actively keeping human CD4⁺ T cells at a resting state.

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 mainly supported by the Alexander von Humboldt Foundation via Sofja-Kovalevskaja Awards (to J.L.S.). T.Z. was supported by the Frauke-Weiskam-Christel Ruranski Foundation and J.L.S. was supported by Grant TV89 from the Center for Molecular Medicine (Cologne, Germany). J.C. was supported by a fellowship from the Mildred Scheel Foundation from the Deutsche Krebshilfe. J.L.S. is a member of the Nationales Genomforschungsnetz (N1KR-S24T27).

² S.C., T.Z., J.M.C., and J.L.S. designed the research. S.C., T.Z., J.M.C., I.B., A.P., M.B., and S.D. performed the research. S.C., T.Z., D.E., J.M.C., B.B., I.B., A.P., M.B., R.E., S.D., and J.L.S. analyzed the data. S.C., T.Z., D.E., B.B., R.E., and S.D. contributed reagents, material, and analysis tools. S.C., T.Z., D.E., and J.L.S. wrote the article.

³ S.C. and T.Z. contributed equally to this work.

⁴ Address correspondence and reprint requests to Dr. Joachim L. Schultze, Department of Internal Medicine I, Molecular Tumor Biology and Tumor Immunology, University of Cologne, Joseph-Stelzmann-Strasse 9, 50931 Cologne, Germany. E-mail address: Joachim.Schultze{at}uk-koeln.de

⁵ Abbreviations used in this paper: GO, gene ontology; ID, identification; aAPC, artificial APC; FC, fold change; PIGF, phosphatidylinositol glycan class F.