Purinergic control of T cell activation by ATP released through pannexin-1 hemichannels.
T cell receptor (TCR) stimulation results in the influx of Ca(2+), which is buffered by mitochondria and promotes adenosine triphosphate (ATP) synthesis. We found that ATP released from activated T cells through pannexin-1 hemichannels activated purinergic P2X receptors (P2XRs) to sustain mitogen-activated protein kinase (MAPK) signaling. P2XR antagonists, such as oxidized ATP (oATP), blunted MAPK activation in stimulated T cells, but did not affect the nuclear translocation of the transcription factor nuclear factor of activated T cells, thus promoting T cell anergy. In vivo administration of oATP blocked the onset of diabetes mediated by anti-islet TCR transgenic T cells and impaired the development of colitogenic T cells in inflammatory bowel disease. Thus, pharmacological inhibition of ATP release and signaling could be beneficial in treating T cell-mediated inflammatory diseases.
Schenk
Ursula
U
Institute for Research in Biomedicine, 6500 Bellinzona, Switzerland.
Westendorf
Astrid M
AM
Radaelli
Enrico
E
Casati
Anna
A
Ferro
Micol
M
Fumagalli
Marta
M
Verderio
Claudia
C
Buer
Jan
J
Scanziani
Eugenio
E
Grassi
Fabio
F
D021581:Active Transport, Cell Nucleus; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000096:biosynthesis* / Q000494:pharmacology; D000818:Animals; D019898:Autocrine Communication; D002118:Calcium / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D017630:Connexins / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology*
D017630:Connexins; D007376:Interleukin-2; D009419:Nerve Tissue Proteins; C503631:Panx1 protein, mouse; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; C017199:2',3'-dialdehyde ATP; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D002118:Calcium