title: Extracellular ATP exerts opposite effects on activated and regulatory CD4+ T cells via purinergic P2 receptor activation.
abstract: It has been reported that ATP inhibits or stimulates lymphoid cell proliferation depending on the cellular subset analyzed. In this study, we show that ATP exerts strikingly opposite effects on anti-CD3/CD28-activated and regulatory CD4(+) T cells (T(regs)), based on nucleotide concentration. We demonstrate that physiological concentrations of extracellular ATP (1-50 nM) do not affect activated CD4(+) T cells and T(regs). Conversely, higher ATP concentrations have a bimodal effect on activated CD4(+) T cells. Whereas 250 nM ATP stimulates proliferation, cytokine release, expression of adhesion molecules, and adhesion, 1 mM ATP induces apoptosis and inhibits activated CD4(+) T cell functions. The expression analysis and pharmacological profile of purinergic P2 receptors for extracellular nucleotides suggest that activated CD4(+) T cells are induced to apoptosis via the upregulation and engagement of P2X7R and P2X4R. On the contrary, 1 mM ATP enhances proliferation, adhesion, migration, via P2Y2R activation, and immunosuppressive ability of T(regs). Similar results were obtained when activated CD4(+) T cells and T(regs) were exposed to ATP released by necrotized leukemic cells. Taken together, our results show that different concentrations of extracellular ATP modulate CD4(+) T cells according to their activated/regulatory status. Because extracellular ATP concentration highly increases in fast-growing tumors or hyperinflamed tissues, the manipulation of purinergic signaling might represent a new therapeutic target to shift the balance between activated CD4(+) T cells and T(regs).
authors: Department of Hematology and Oncological Sciences L. & A. Seràgnoli, University of Bologna, 9-40138 Bologna, Italy. sara.trabanelli@gmail.com
authors: Sara
authors: S
authors: Trabanelli
authors: Darina
authors: D
authors: Ocadlíková
authors: Sara
authors: S
authors: Gulinelli
authors: Antonio
authors: A
authors: Curti
authors: Valentina
authors: V
authors: Salvestrini
authors: Rodolfo de Paula
authors: RP
authors: Vieira
authors: Marco
authors: M
authors: Idzko
authors: Francesco
authors: F
authors: Di Virgilio
authors: Davide
authors: D
authors: Ferrari
authors: Roberto M
authors: RM
authors: Lemoli
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology*; D017209:Apoptosis / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000276:immunology; D016923:Cell Death / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D045604:Extracellular Fluid / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology*; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*
chemical_list: D018048:Receptors, Purinergic P2; D000255:Adenosine Triphosphate