title: Time-Dependent Regulation of IL-2R α-Chain (CD25) Expression by TCR Signal Strength and IL-2-Induced STAT5 Signaling in Activated Human Blood T Lymphocytes.
abstract: The expression of the IL-2R α-chain (IL-2Rα) is regulated at the transcriptional level via TCR- and IL-2R-signaling. The question is how to precede in time the activation signals to induce the IL-2Rα expression in native primary T cells. By comparing the effects of selective drugs on the dynamics of CD25 expression during the mitogen stimulation of human peripheral blood lymphocytes, we identified distinct Src- and JAK-dependent stages of IL-2Rα upregulation. PP2, a selective inhibitor of TCR-associated Src kinase, prevents CD25 expression at initial stages of T cell activation, prior to the cell growth. This early IL-2Rα upregulation underlies the T cell competence and the IL-2 responsiveness. We found that the activated with "weak" mitogen, the population of blood lymphocytes has some pool of competent CD25+ cells bearing a high affinity IL-2R. A distinct pattern of IL-2R signaling in resting and competent T lymphocytes has been shown. Based on the inhibitory effect of WHI-P131, a selective drug of JAK3 kinase activity, we concluded that in quiescent primary T lymphocytes, the constitutive STAT3 and the IL-2-induced prolonged STAT5 activity (assayed by tyrosine phosphorylation) is mostly JAK3-independent. In competent T cells, in the presence of IL-2 JAK3/STAT5 pathway is switched to maintain the higher and sustained IL-2Rα expression as well as cell growth and proliferation. We believe that understanding the temporal coordination of antigen- and cytokine-evoked signals in primary T cells may be useful for improving immunotherapeutic strategies.
authors.affiliation: Department of Intracellular Signaling and Transport, Institute of Cytology, Russian Academy of Sciences, St-Petersburg, Russia.
authors.forename: Alla N
authors.initials: AN
authors.lastname: Shatrova
authors.affiliation: Department of Intracellular Signaling and Transport, Institute of Cytology, Russian Academy of Sciences, St-Petersburg, Russia.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Mityushova
authors.affiliation: Department of Intracellular Signaling and Transport, Institute of Cytology, Russian Academy of Sciences, St-Petersburg, Russia.
authors.forename: Irina O
authors.initials: IO
authors.lastname: Vassilieva
authors.affiliation: Department of Intracellular Signaling and Transport, Institute of Cytology, Russian Academy of Sciences, St-Petersburg, Russia.
authors.forename: Nikolay D
authors.initials: ND
authors.lastname: Aksenov
authors.affiliation: Department of Intracellular Signaling and Transport, Institute of Cytology, Russian Academy of Sciences, St-Petersburg, Russia.
authors.forename: Valery V
authors.initials: VV
authors.lastname: Zenin
authors.affiliation: Department of Intracellular Signaling and Transport, Institute of Cytology, Russian Academy of Sciences, St-Petersburg, Russia.
authors.forename: Nikolay N
authors.initials: NN
authors.lastname: Nikolsky
authors.affiliation: Department of Intracellular Signaling and Transport, Institute of Cytology, Russian Academy of Sciences, St-Petersburg, Russia.
authors.forename: Irina I
authors.initials: II
authors.lastname: Marakhova
mesh_terms: D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism*; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008213:Lymphocyte Activation; D010766:Phosphorylation / Q000187:drug effects; D010835:Phytohemagglutinins / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000378:metabolism*; D013997:Time Factors
chemical_list: D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D010835:Phytohemagglutinins; D011799:Quinazolines; D011948:Receptors, Antigen, T-Cell; D050799:STAT5 Transcription Factor; C116180:WHI P131; C507933:JAK3 protein, human; D053616:Janus Kinase 3