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

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Abstract
Although the β2-adrenergic receptor (β2AR) is the most extensively characterized G-protein-coupled receptor (GPCR), the effects of β-agonists on T-cell subtype function remain poorly understood. In contrast to studies suggesting lack of β2AR 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 β-agonist, with effects including induction of protein kinase A (PKA) activity and associated inhibition of CD3-stimulated CD25 expression; CD3-stimulated IL-13, interferon-γ (IFN-γ), and IL-2 production; and p38 mitogen-activated protein kinase (MAPK) phosphorylation. PGE2 was more efficacious than β-agonist in activating PKA and inhibiting cytokine production. β-agonist and PGE2 also inhibited phorbol myristate acetate (PMA) + calcimycin-stimulated IFN-γ 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-κB explained the capacity of PGE2 and β-agonist to inhibit IFN-γ but not IL-13 production. The inhibition of CD3 + CD28-stimulated IL-13 production by both β-agonist and PGE2 was reversed at low agonist concentrations, resulting in enhanced IL-13, but not IFN-γ or IL-2, production. These findings identify direct effects of β2AR activation on T-cell subtypes and suggest a complex role for GPCRs and PKA activity in modulating T-cell functions.