Pannexin-1 hemichannel-mediated ATP release together with P2X1 and P2X4 receptors regulate T-cell activation at the immune synapse.
Engagement of T cells with antigen-presenting cells requires T-cell receptor (TCR) stimulation at the immune synapse. We previously reported that TCR stimulation induces the release of cellular adenosine-5'-triphosphate (ATP) that regulates T-cell activation. Here we tested the roles of pannexin-1 hemichannels, which have been implicated in ATP release, and of various P2X receptors, which serve as ATP-gated Ca(2+) channels, in events that control T-cell activation. TCR stimulation results in the translocation of P2X1 and P2X4 receptors and pannexin-1 hemichannels to the immune synapse, while P2X7 receptors remain uniformly distributed on the cell surface. Removal of extracellular ATP or inhibition, mutation, or silencing of P2X1 and P2X4 receptors inhibits Ca(2+) entry, nuclear factors of activated T cells (NFAT) activation, and induction of interleukin-2 synthesis. Inhibition of pannexin-1 hemichannels suppresses TCR-induced ATP release, Ca(2+) entry, and T-cell activation. We conclude that pannexin-1 hemichannels and P2X1 and P2X4 receptors facilitate ATP release and autocrine feedback mechanisms that control Ca(2+) entry and T-cell activation at the immune synapse.
Woehrle
Tobias
T
Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
Yip
Linda
L
Elkhal
Abdallah
A
Sumi
Yuka
Y
Chen
Yu
Y
Yao
Yongli
Y
Insel
Paul A
PA
Junger
Wolfgang G
WG
D000255:Adenosine Triphosphate / Q000276:immunology*; D002118:Calcium / Q000276:immunology; D015220:Calcium Channels / Q000235:genetics; D017630:Connexins / Q000276:immunology* / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D054992:Immunological Synapses / Q000276:immunology* / Q000648:ultrastructure; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000235:genetics; D050778:NFATC Transcription Factors / Q000276:immunology; D009363:Neoplasm Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000276:immunology* / Q000378:metabolism; D000071740:ORAI1 Protein; D021381:Protein Transport; D058474:Receptors, Purinergic P2X1 / Q000235:genetics / Q000276:immunology*; D058848:Receptors, Purinergic P2X4 / Q000235:genetics / Q000276:immunology*; D058485:Receptors, Purinergic P2X5 / Q000235:genetics / Q000276:immunology; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000276:immunology; D000071737:Stromal Interaction Molecule 1; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure
D015220:Calcium Channels; D017630:Connexins; D007376:Interleukin-2; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C492764:PANX1 protein, human; D058474:Receptors, Purinergic P2X1; D058848:Receptors, Purinergic P2X4; D058485:Receptors, Purinergic P2X5; D058486:Receptors, Purinergic P2X7; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D000255:Adenosine Triphosphate; D002118:Calcium