Beta-agonists modulate T-cell functions via direct actions on type 1 and type 2 cells

Although the beta(2)-adrenergic receptor (beta(2)AR) is the most extensively characterized G-protein-coupled receptor (GPCR), the effects of beta-agonists on T-cell subtype function remain poorly understood. In contrast to studies suggesting lack of beta(2)AR expression on type 2 T cells, we demonstrate that type 2 interleukin-13(+) (IL-13(+)) T cells (CD4(+) or CD8(+)) in human peripheral blood lymphocytes (PBLs) can respond directly to beta-agonist, with effects including induction of protein kinase A (PKA) activity and associated inhibition of CD3-stimulated CD25 expression; CD3-stimulated IL-13, interferon-gamma (IFN-gamma), and IL-2 production; and p38 mitogen-activated protein kinase (MAPK) phosphorylation. PGE(2) was more efficacious than p-agonist in activating PKA and inhibiting cytokine production. P-agonist and PGE2 also inhibited phorbol myristate acetate (PMA) + calcimycin-stimulated IFN-gamma and IL-2 (but not IL-13) production, suggesting that upstream CD3-initiated signaling is not the sole locus of PKA actions. Differential regulation of PMA-stimulated p38, p42/p44, and NF-kappa B explained the capacity of PGE(2) and beta-agonist to inhibit IFN-gamma but not IL-13 production. The inhibition of CD3 + CD28-stimulated IL-13 production by both beta-agonist and PGE(2) was reversed at low agonist concentrations, resulting in enhanced IL-13, but not IFN-gamma or IL-2, production. These findings identify direct effects of beta(2)AR activation on T-cell subtypes and suggest a complex role for GPCRs and PKA activity in modulating T-cell functions.