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Sci. Signal., 20 December 2011
Vol. 4, Issue 204, p. ra90
[DOI: 10.1126/scisignal.2002179]

RESEARCH ARTICLES

Human Regulatory T Cells Rapidly Suppress T Cell Receptor–Induced Ca2+, NF-{kappa}B, and NFAT Signaling in Conventional T Cells

Angelika Schmidt1*, Nina Oberle1*, Eva-Maria Weiß1, Diana Vobis1, Stefan Frischbutter2, Ria Baumgrass2, Christine S. Falk3, Mathias Haag4, Britta Brügger4, Hongying Lin5, Georg W. Mayr5, Peter Reichardt6, Matthias Gunzer6, Elisabeth Suri-Payer1, and Peter H. Krammer1{dagger}

1 Division of Immunogenetics (D030), Tumor Immunology Program, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
2 Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, 10117 Berlin, Germany.
3 Institute for Transplant Immunology, OE 8889, Hannover Medical School, 30625 Hanover, Germany.
4 Heidelberg University Biochemistry Center, 69120 Heidelberg, Germany.
5 Institut für Biochemie und Signaltransduktion, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
6 Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University-Magdeburg, 39120 Magdeburg, Germany.

* These authors contributed equally to this work.

Abstract: CD4+CD25hiFoxp3+ regulatory T cells (Tregs) are critical mediators of self-tolerance, which is crucial for the prevention of autoimmune disease, but Tregs can also inhibit antitumor immunity. Tregs inhibit the proliferation of CD4+CD25 conventional T cells (Tcons), as well as the ability of these cells to produce effector cytokines; however, the molecular mechanism of suppression remains unclear. Here, we showed that human Tregs rapidly suppressed the release of calcium ions (Ca2+) from intracellular stores in response to T cell receptor (TCR) activation in Tcons. The inhibition of Ca2+ signaling resulted in decreased dephosphorylation, and thus decreased activation, of the transcription factor nuclear factor of activated T cells 1 (NFAT1) and reduced the activation of nuclear factor {kappa}B (NF-{kappa}B). In contrast, Ca2+-independent events in Tcons, such as TCR-proximal signaling and activation of the transcription factor activator protein 1 (AP-1), were not affected during coculture with Tregs. Despite suppressing intracellular Ca2+ mobilization, coculture with Tregs did not block the generation of inositol 1,4,5-trisphosphate in TCR-stimulated Tcons. The Treg-induced suppression of the activity of NFAT and NF-{kappa}B and of the expression of the gene encoding the cytokine interleukin-2 was reversed in Tcons by increasing the concentration of intracellular Ca2+. Our results elucidate a previously unrecognized and rapid mechanism of Treg-mediated suppression. This increased understanding of Treg function may be exploited to generate possible therapies for the treatment of autoimmune diseases and cancer.

{dagger} To whom correspondence should be addressed. E-mail: P.Krammer{at}dkfz.de

Citation: A. Schmidt, N. Oberle, E.-M. Weiß, D. Vobis, S. Frischbutter, R. Baumgrass, C. S. Falk, M. Haag, B. Brügger, H. Lin, G. W. Mayr, P. Reichardt, M. Gunzer, E. Suri-Payer, P. H. Krammer, Human Regulatory T Cells Rapidly Suppress T Cell Receptor–Induced Ca2+, NF-{kappa}B, and NFAT Signaling in Conventional T Cells. Sci. Signal. 4, ra90 (2011).

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