Abstract
Glucocorticoids are potent immunosuppressive agents that block upstream signaling events required for T cell receptor (TCR) activation. However, the mechanism by which glucocorticoids inhibit downstream responses, such as inositol 1,4,5-trisphosphate (IP(3))-induced calcium signals, is not completely understood. Here we demonstrate that low concentrations of dexamethasone rapidly convert transient calcium elevations to oscillations after strong TCR stimulation. Dexamethasone converted the pattern of calcium signaling by inhibiting the Src family kinase Lck, which was shown to interact with and positively regulate Type I IP(3) receptor. In addition, low concentrations of dexamethasone were sufficient to inhibit calcium oscillations and interleukin-2 mRNA after weak TCR stimulation. Together, these findings indicate that by inhibiting Lck and subsequently down-regulating IP(3) receptors, glucocorticoids suppress immune responses by weakening the strength of the TCR signal.
Highlights
Glucocorticoids are among the most widely prescribed immunosuppressive agents, due in part to their remarkable ability to inhibit synthesis of pro-inflammatory cytokines such as IL-22 [1,2,3]
In the present study we found that 30 – 60 min of exposure to low concentrations (1–10 nM) of dexamethasone converted calcium signaling patterns from transient to oscillatory after strong T cell receptor (TCR) stimulation and inhibited oscillations induced by weak TCR stimulation
Strong and Weak TCR Stimulation Induce Distinct Patterns of Calcium Signaling—Immature T cells are highly sensitive to calcium responses induced by anti-TCR antibodies
Summary
TCR stimulation induces calcium release from the ER to the cytosol by way of IP3 receptor channels [12] This process is mediated, in part, by the Src family kinase Lck, which is abundantly expressed in immature double positive T cells [14]. Glucocorticoids Modulate Calcium Signals over, calcium responses were mediated in part by a proteinprotein interaction between Lck and Type I IP3 receptor, and loss of Lck expression or activity resulted in IP3 receptor downregulation Together these data suggest that glucocorticoidmediated inhibition of Lck controls the pattern of TCR responses by negatively regulating IP3 receptor expression. These data provide a novel mechanism by which glucocorticoids function to inhibit calcium signaling to suppress TCR stimulation
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