Costimulation with Dexamethasone and Prostaglandin E2: A Novel Paradigm for the Induction of T-Cell Anergy

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In this report, data are presented which indicate that anti-CD3 mAb-stimulated human peripheral blood T-cells treated with both dexamethasone (DEX) and prostaglandin E2(PGE2) become anergic. This anergy can be reversed by the addition of IL-2. Further, experiments were performed to investigate this T-cell anergy. The results show that addition of DEX and PGE2to anti-CD3 mAb-stimulated T-cells inhibits the induction of p56lckbut not p59fynkinase activity nor is the tyrosine phosphorylation of PLCγ altered appreciably. Additionally, this treatment of anti-CD3 mAb-stimulated T-cells also results in decreased tyrosine phosphorylation of ERK1, suggesting that the Ras activation pathway may be inhibited. Interestingly, the induction of T-cell anergy is reproduced when an agonist for the cAMP-independent EP3subtype of the PGE2receptor is substituted for PGE2. Thus, while the mechanisms responsible for the dual action of DEX and PGE2on the induction of T-cell anergy is unknown, these data suggest that a cAMP-independent mechanism may be involved. These data indicate that a state of anergy can be induced in normal human T-cells by the activation of these cells in the presence of physiologic concentrations of DEX and PGE2.