Human regulatory T cells rapidly suppress T cell receptor-induced calcium, NF-κB, and NFAT signaling in conventional T cells
Angelika
Schmidt1, 2*,
Nina
Oberle2,
Rubin
N.
Joshi1,
Hongying
Lin3,
Georg
W.
Mayr3,
Stefan
Frischbutter4,
Ria
Baumgrass4,
Nadine
A.
Binai5,
Arjen
Scholten5,
Elisabeth
Suri-Payer2,
Jesper
Tegnér1 and
Peter
H.
Krammer2
-
1
Karolinska Institutet, Karolinska University Hospital, Department of Medicine, Solna, Sweden
-
2
German Cancer Research Center (DKFZ), Division of Immunogenetics, Germany
-
3
University Medical Center Hamburg-Eppendorf, Institut für Biochemie und Signaltransduktion, Germany
-
4
Deutsches Rheuma-Forschungszentrum (DRFZ), a Leibniz Institute, Germany
-
5
Utrecht University, Biomolecular Mass Spectrometry and Proteomics group, Netherlands
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 dampen 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 mechanisms of suppression remain incompletely understood. We show 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 kB (NF-kB). In contrast, Ca2+-independent events in Tcons, such as TCR-proximal signaling and activation of 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-kB and of the expression of IL-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. Ongoing and future studies aim at deciphering new molecules causative for this rapid suppression by next-generation proteomics studies, pathway analyses and computational data integration. This increased understanding of Treg function and Tcon resistance to suppression may be exploited to generate possible therapies for the treatment of autoimmune diseases and cancer.
References
Schmidt,A., Oberle,N., Weiß,E.-M., Vobis,D., Frischbutter,S., Baumgrass,R., Falk,C.S., Haag,M., Brügger,B., Lin,H., Mayr,G.W., Reichardt,P., Gunzer,M., Suri-Payer,E., and Krammer,P.H. (2011). Human regulatory T cells rapidly suppress T cell receptor–induced Ca2+, NF-kB, and NFAT signaling in conventional T cells. Sci. Signal. 4, ra90.
Keywords:
Treg,
TCR signaling,
regulatory T cells,
Calcium,
NFAT,
NF-kappa B,
suppression mechanisms
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Immune receptors and signaling
Citation:
Schmidt
A,
Oberle
N,
Joshi
RN,
Lin
H,
Mayr
GW,
Frischbutter
S,
Baumgrass
R,
Binai
NA,
Scholten
A,
Suri-Payer
E,
Tegnér
J and
Krammer
PH
(2013). Human regulatory T cells rapidly suppress T cell receptor-induced calcium, NF-κB, and NFAT signaling in conventional T cells.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00515
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Received:
11 Jun 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Dr. Angelika Schmidt, Karolinska Institutet, Karolinska University Hospital, Department of Medicine, Solna, Stockholm, Sweden, schmidt_angelika@outlook.com