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Sci. Signal., 1 March 2011
Vol. 4, Issue 162, p. ra12
[DOI: 10.1126/scisignal.2001270]

RESEARCH ARTICLES

ATP Inhibits the Generation and Function of Regulatory T Cells Through the Activation of Purinergic P2X Receptors

Ursula Schenk1*, Michela Frascoli1, Michele Proietti1, Robert Geffers2, Elisabetta Traggiai3, Jan Buer4, Camillo Ricordi5, Astrid M. Westendorf4, and Fabio Grassi1,6{dagger}

1 Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland.
2 Department of Cell Biology, Helmholtz Centre for Infection Research, D-38124 Braunschweig, Germany.
3 Istituto Giannina Gaslini, I-16147 Genoa, Italy.
4 Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, D-45122 Essen, Germany.
5 Cell Transplant Center and Diabetes Research Institute, University of Miami, Miami, FL 33136, USA.
6 Dipartimento di Biologia e Genetica per le Scienze Mediche, Università degli Studi di Milano, I-20133 Milano, Italy.

* Present address: Pharmanalytica SA, CH-6601 Locarno, Switzerland.

Abstract: Extracellular nucleotides are pleiotropic regulators of mammalian cell function. Adenosine triphosphate (ATP) released from CD4+ helper T cells upon stimulation of the T cell receptor (TCR) contributes in an autocrine manner to the activation of mitogen-activated protein kinase (MAPK) signaling through purinergic P2X receptors. Increased expression of p2rx7, which encodes the purinergic receptor P2X7, is part of the transcriptional signature of immunosuppressive CD4+CD25+ regulatory T cells (Tregs). Here, we show that the activation of P2X7 by ATP inhibits the suppressive potential and stability of Tregs. The inflammatory cytokine interleukin-6 (IL-6) increased ATP synthesis and P2X7-mediated signaling in Tregs, which induced their conversion to IL-17–secreting T helper 17 (TH17) effector cells in vivo. Moreover, pharmacological antagonism of P2X receptors promoted the cell-autonomous conversion of naïve CD4+ T cells into Tregs after TCR stimulation. Thus, ATP acts as an autocrine factor that integrates stimuli from the microenvironment and cellular energetics to tune the developmental and immunosuppressive program of the T cell in adaptive immune responses.

{dagger} To whom correspondence should be addressed. E-mail: fabio.grassi{at}irb.unisi.ch

Citation: U. Schenk, M. Frascoli, M. Proietti, R. Geffers, E. Traggiai, J. Buer, C. Ricordi, A. M. Westendorf, F. Grassi, ATP Inhibits the Generation and Function of Regulatory T Cells Through the Activation of Purinergic P2X Receptors. Sci. Signal. 4, ra12 (2011).

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