ATP inhibits the generation and function of regulatory T cells through the activation of purinergic P2X receptors

Ursula Schenk, Michela Frascoli, Michele Proietti, Robert Geffers, Elisabetta Traggiai, Jan Buer, Camillo Ricordi, Astrid M. Westendorf, Fabio Grassi

Research output: Contribution to journalArticle

145 Scopus citations

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 (T regs). 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.

Original languageEnglish (US)
Article numberra12
JournalScience Signaling
Volume4
Issue number162
DOIs
StatePublished - Mar 1 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Schenk, U., Frascoli, M., Proietti, M., Geffers, R., Traggiai, E., Buer, J., Ricordi, C., Westendorf, A. M., & Grassi, F. (2011). ATP inhibits the generation and function of regulatory T cells through the activation of purinergic P2X receptors. Science Signaling, 4(162), [ra12]. https://doi.org/10.1126/scisignal.2001270