Abstract
Peripheral homeostasis and tolerance requires the suppression or removal of excessive or harmful T lymphocytes. This can occur either by apoptosis through active antigen-induced death or cytokine withdrawal. Alternatively, T cell activation can be suppressed by agents that activate the cAMP-dependent protein kinase (PKA) signaling pathway, such as prostaglandin E2. Stimulation of PKA inhibits lymphocyte proliferation and immune effector functions. Here we have investigated the mechanism by which activation of PKA induces inhibition of proliferation in human leukemic T cell lines. Using a variety of agents that stimulate PKA, we can arrest Jurkat and H9 leukemic T cells in the G(1) phase of the cell cycle, whereas cell viability is hardly affected. This G(1) arrest is associated with an inhibition of cyclin D/Cdk and cyclin E/Cdk kinase activity. Interestingly, expression of cyclin D3 is rapidly reduced by PKA activation, whereas expression of the Cdk inhibitor p27(kip1) is induced. Ectopic expression of cyclin D3 can override the growth suppression induced by PKA activation to some extent, indicating that growth inhibition of leukemic T cells by PKA activation is partially dependent on down-regulation of cyclin D3 expression. Taken together our data suggest that immunosuppression by protein kinase A involves regulation of both cyclin D3 and p27(kip1) expression.
Highlights
Exposure to an antigen elicits a dramatic expansion of resting peripheral T lymphocytes that recognize and target this antigen
We have used these cell lines as a model to study protein kinase (PKA)-mediated immunosuppression. We show that these cells are inhibited in their growth by agents that activate PKA and show that expression of cyclin D3 is down-regulated in leukemic T cell lines in response to activation of PKA
In this report we have addressed the mechanism of suppression of T cell proliferation in response to activation of PKA
Summary
Exposure to an antigen elicits a dramatic expansion of resting peripheral T lymphocytes that recognize and target this antigen. We show that these cells are inhibited in their growth by agents that activate PKA and show that expression of cyclin D3 is down-regulated in leukemic T cell lines in response to activation of PKA. PKA Stimulation Causes a G1 Arrest but Does Not Affect Cell Viability—Cross-linking of the CD3 complex on leukemic T cell lines can result in programmed cell death [13,14,15], and we previously showed that the TCR-induced growth inhibition of Jurkat cells is in part due to a reduction in cell viability [13].
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