An ATP-activated channel is involved in mitogenic stimulation of human T lymphocytes

Abstract

We investigated the effect of pharmacologic modulation of the ATP receptor on intracellular ion changes and proliferative response of human peripheral blood lymphocytes (PBLs) and purified T lymphocytes. Extracellular ATP (ATPe) triggered in these cells an increase in the cytoplasmic Ca2+ concentration ([Ca2+]i) and plasma membrane depolarization. Whereas both Ca2+ release from intracellular stores and influx across the plasma membrane were detected in the whole PBL population, only Ca2+ influx was observed in T cells. In the presence of near physiologic extracellular Na+ concentrations (125 mmol/L), Ca2+ permeability through the ATPe-gated channel was very low, suggesting a higher selectivity for monovalent over divalent cations. The selective P2Z agonist benzoylbenzoic ATP (BzATP) increased [Ca2+]i in the presence but not the absence of extracellular Ca2+ and also caused plasma membrane depolarization. The covalent blocker oxidized ATP (oATP), an inhibitor of P2X and P2Z receptors, prevented Ca2+ influx and plasma membrane depolarization, but had no effect on Ca2+ release from stores. Stimulation with ATPe alone had no significant effects on PBL 3H-thymidine incorporation. On the contrary, ATPe or BzATP had a synergistic effect on DNA synthesis stimulated by selective T-cell mitogens such as phytohemagglutinin, anti-CD3 monoclonal antibody, or allogenic PBLs (mixed lymphocyte cultures). Treatment with oATP inhibited mitogenic stimulation by these receptor-directed agents but not by the combined application of the Ca2+ ionophore ionomycin and phorbol myristate acetate. Interleukin-2 partially relieved inhibition by oATP. These results suggest that human T lymphocytes express a plasma membrane channel gated by ATPe that is involved in mitogenic stimulation.

Trophic activity of a naturally occurring truncated isoform of the P2X7 receptor

“…We were intrigued by the high expression level of P2X7B in lymphocytes, a cell type that is known to express P2X7, but to be refractory to ATP-mediated plasma membrane permeabilization (13,32), the functional signature of the P2X7 receptor. This observation lead us to hypothesize some time ago that lymphocytes might express an "atypical" P2X7 receptor (32,33). The present data showing that the truncated isoform B is highly expressed in lymphocytes suggest that our hypothesis was not too far from the truth.…”

Autocrine regulation of T‐cell activation by ATP release and P2X7receptors

“…Thus, the lower P2X 7 receptor expression in Jurkat cells, a cell line originally derived from a patient with acute T-cell leukemia, may protect the cells from apoptosis and thereby contribute to their growth. P2X 7 receptor expression correlates with cell proliferation (23,26), implying that the apoptotic vs. proliferative roles of P2X 7 receptors differ among different types of T cells.…”

“…While previous studies have shown that prolonged stimulation of P2X 7 receptors with high concentrations of ATP induces cellular apoptosis (15,(23)(24)(25), transient stimulation of T cells with lower ATP concentrations, such as those secreted in an autocrine or paracrine fashion, can stimulate T-cell proliferation (23). Under such conditions, overexpression of P2X 7 receptors can further promote T-cell proliferation (23,26). Our previous work using Jurkat T cells has demonstrated that osmotic stress induces the release of endogenous ATP, which achieves extracellular concentrations of ϳ10 M (3).…”

Reduced IL-10 secretion by CD4+ T lymphocytes expressing mutant cystic fibrosis transmembrane conductance regulator (CFTR)

“…The CF cell would lack this regulatory mechanism and be subject to maximal Ca 2 influx, which would have a differential suppressive effect on IL-10 secretion. An alternative mechanism could involve the effect of extracellular ATP (ATP e ) on T cell activation [54], since CFTR regulates extracellular ATP e in an as yet unspecified manner [40,55,56]. The effect of ATP e on cytokine secretion has not been reported.…”