Costimulation with dexamethasone and prostaglandin E-2: A novel paradigm for the induction of T-cell anergy

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 E-2 (PGE(2)) 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 PGE(2) to anti-CD3 mAb-stimulated T-cells inhibits the induction of p56(lck) but not p59(fyn) kinase activity nor is the tyrosine phosphorylation of PLC gamma 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 EP3 subtype of the PGE(2) receptor is substituted for PGE(2). Thus, while the mechanisms responsible for the dual action of DEX and PGE(2) on 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 PGE(2). (C) 1997 Academic Press.