title: ATP release and autocrine signaling through P2X4 receptors regulate γδ T cell activation.
abstract: Purinergic signaling plays a key role in a variety of physiological functions, including regulation of immune responses. Conventional αβ T cells release ATP upon TCR cross-linking; ATP binds to purinergic receptors expressed by these cells and triggers T cell activation in an autocrine and paracrine manner. Here, we studied whether similar purinergic signaling pathways also operate in the "unconventional" γδ T lymphocytes. We observed that γδ T cells purified from peripheral human blood rapidly release ATP upon in vitro stimulation with anti-CD3/CD28-coated beads or IPP. Pretreatment of γδ T cells with (10)panx-1, CBX, or Bf A reversed the stimulation-induced increase in extracellular ATP concentration, indicating that panx-1, connexin hemichannels, and vesicular exocytosis contribute to the controlled release of cellular ATP. Blockade of ATP release with (10)panx-1 inhibited Ca(2+) signaling in response to TCR stimulation. qPCR revealed that γδ T cells predominantly express purinergic receptor subtypes A2a, P2X1, P2X4, P2X7, and P2Y11. We found that pharmacological inhibition of P2X4 receptors with TNP-ATP inhibited transcriptional up-regulation of TNF-α and IFN-γ in γδ T cells stimulated with anti-CD3/CD28-coated beads or IPP. Our data thus indicate that purinergic signaling via P2X4 receptors plays an important role in orchestrating the functional response of circulating human γδ T cells.
authors: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors: Monali
authors: M
authors: Manohar
authors: Mark I
authors: MI
authors: Hirsh
authors: Yu
authors: Y
authors: Chen
authors: Tobias
authors: T
authors: Woehrle
authors: Anjali A
authors: AA
authors: Karande
authors: Wolfgang G
authors: WG
authors: Junger
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D019898:Autocrine Communication / Q000502:physiology*; D018106:CD28 Antigens / Q000502:physiology; D017252:CD3 Complex / Q000502:physiology; D020013:Calcium Signaling; D005089:Exocytosis; D006801:Humans; D008213:Lymphocyte Activation; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000502:physiology*; D058848:Receptors, Purinergic P2X4 / Q000032:analysis / Q000502:physiology*; D058486:Receptors, Purinergic P2X7 / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; D016692:Receptors, Antigen, T-Cell, gamma-delta; D058848:Receptors, Purinergic P2X4; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate