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,
* Department of Surgery,
Department of Pharmacology, and
Department of Medicine, University of California San Diego, San Diego, California, USA;
Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, California, USA; and
|| Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
1Correspondence: Beth Israel Deaconess Medical Center, Harvard Medical School, Department of Surgery, 330 Brookline Ave. E/ST-8M10C, Boston, MA 02215, USA. E-mail: wjunger{at}bidmc.harvard.edu
T-cell activation requires the influx of extracellular calcium, although mechanistic details regarding such activation are not fully defined. Here, we show that P2X7 receptors play a key role in calcium influx and downstream signaling events associated with the activation of T cells. By real-time PCR and immunohistochemistry, we find that Jurkat T cells and human CD4+ T cells express abundant P2X7 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 P2X7 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 P2X7 receptors blocks calcium entry and inhibits T-cell activation. Moreover, lymphocyte activation is impaired in C57BL/6 mice that express poorly functional P2X7 receptors, compared to control BALB/c mice, which express fully functional P2X7 receptors. We conclude that ATP release and autocrine, positive feedback through P2X7 receptors is required for the effective activation of T cells.—Yip, L., Woehrle, 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.
Key Words: interleukin-2 • NFAT • calcium signaling • real-time PCR • siRNA silencing
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