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.
Highlights
T cell activation involves two major steps of signal transduction events
We studied time- and dose-dependent relations between drug-inhibitable portions of CD25 expression and present new evidence that under physiological conditions in quiescent human T cells, induction of IL-2 receptor α-chain (IL-2Rα) is timely regulated by two independent signals via T cell receptor (TCR) and high-affinity IL-2R
To determine directly whether IL-2R signaling is necessary for CD25 expression in intact T-lymphocytes, we used WHI-P131 (4-(4 ́-Hydroxyphenyl)amino-6,7-dimethoxyquinozoline) as an effective inhibitor of IL-2R-associated tyrosine kinase JAK3
Summary
T cell activation involves two major steps of signal transduction events. T cell receptor (TCR) complex upon specific antigen recognition initiates the first signal that regulates the expression of specific genes, including cytokines and cytokine receptors [1,2,3]. TCR-induced expression of interleukin-2 (IL-2) and IL-2 receptor α-chain (IL-2Rα) starts the second wave of signaling events that, result in T cell proliferation through activation of diverse target genes [4, 5]. The expression of the IL-2Rα regulates the magnitude of PLOS ONE | DOI:10.1371/journal.pone.0167215. IL-2Rα expression increases the affinity of IL-2 binding ~100 times, facilitating IL-2 responses at low physiological concentrations of IL-2 [9,10,11]. Compromised expression of IL-2 or IL-2Rα leads to the development of autoimmune diseases and immunodeficiency [12,13,14]
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