Beta2-adrenergic receptor signaling in CD4+ Foxp3+ regulatory T cells enhances their suppressive function in a PKA-dependent manner.

Beta2-adrenergic receptor ( B2 AR) signaling is known to impair Th1-cell differentiation and function in a c AMP-dependent way, leading to inhibition of cell proliferation and decreased production of IL-2 and IFN-γ. CD4⁺ Foxp3⁺ Treg cells play a key role in the regulation of immune responses and are essential for maintenance of self-tolerance. Nevertheless, very little is known about adrenergic receptor expression in Treg cells or the influence of noradrenaline on their function. Here we show that Foxp3⁺ Treg cells express functional B2 AR. B2 AR activation in Treg cells leads to increased intracellular c AMP levels and to protein kinase A ( PKA)-dependent CREB phosphorylation. We also found that signaling via B2 AR enhances the in vitro suppressive activity of Treg cells. B2 AR-mediated increase in Treg-cell suppressive function was associated with decreased IL-2 m RNA levels in responder CD4⁺ T cells and improved Treg-cell-induced conversion of CD4⁺ Foxp3⁻ cells into Foxp3⁺ induced Treg cells. Moreover, B2 AR signaling increased CTLA-4 expression in Treg cells in a PKA-dependent way. Finally, we found that PKA inhibition totally prevented the B2 AR-mediated increase in Treg-cell suppressive function. Our data suggest that sympathetic fibers are able to regulate Treg-cell suppressive activity in a positive manner through B2 AR signaling. [ABSTRACT FROM AUTHOR]