Autocrine regulation of T‐cell activation by ATP release and P2X 7 receptors

ABSTRACT T‐cell activation requires the influx of extracellular calcium, although mechanistic details regarding such activation are not fully defined. Here, we show that P2X 7 receptors play a key role in calcium influx and downstream signaling events associated with the activation of T cells. By real‐time PCR and immu‐nohistochemistry, we find that Jurkat T cells and human CD4 + T cells express abundant P2X 7 receptors. We show, using a novel fluorescent microscopy technique, that T‐cell receptor (TCR) stimulation triggers the rapid release of ATP (<100 μM). This release of ATP is required for TCR‐mediated calcium influx, NFAT activation, and interleukin‐2 (IL‐2) production. TCR activation up‐regulates P2X 7 receptor gene expression. Removal of extracellular ATP by apyrase or alkaline phosphatase treatment, inhibition of ATP release with the maxi‐anion channel blocker gadolinium chloride, or siRNA silencing of P2X 7 receptors blocks calcium entry and inhibits T‐cell activation. Moreover, lymphocyte activation is impaired in C57BL/6 mice that express poorly functional P2X 7 receptors, compared to control BALB/c mice, which express fully functional P2X 7 receptors. We conclude that ATP release and autocrine, positive feedback through P2X 7 receptors is required for the effective activation of T cells.—Yip, L., Woe–hrle, T.,Corriden, R., Hirsh, M., Chen, Y., Inoue, Y., Ferrari, V., Insel, P.A., Junger, W.G. Autocrine regulation of T‐cell activation by ATP release and P2X7 receptors. FASEBJ. 23, 1685–1693 (2009)