Autocrine regulation of T-cell activation by ATP release and P2X(7) receptors

作者：Yip Linda; Woehrle Tobias; Corriden Ross; Hirsh Mark; Chen Yu; Inoue Yoshiaki; Ferrari Vhe; Insel Paul A; Junger Wolfgang G^*

来源：The FASEB Journal, 2009, 23(6): 1685-1693.

DOI：10.1096/fj.08-126458

• interleukin-2
• NFAT
• calcium signaling
• real-time PCR
• siRNA silencing

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 immunohistochemistry, 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 mu M). 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., 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. FASEB J. 23, 1685-1693 (2009)

• 出版日期2009-6