Beta-2 adrenergic receptors increase TREG cell suppression in an OVA-induced allergic asthma mouse model when mice are moderate aerobically exercised

Background: The potency of T regulatory (TREG) cells to inhibit T helper (Th)-driven immune cell responses has been linked to increased intracellular cyclic-AMP (cAMP) levels of TREG cells. In an ovalbumin (OVA)-driven allergic asthma mouse model, moderate aerobic exercise increases TREG cell function in a contact-dependent manner that leads to a significant reduction in chronic inflammation and restoration of lung function. However, the mechanism, whereby exercise increases TREG function, remains unknown and was the focus of these investigations. Exercise can communicate with TREG cells by their expression of beta 2-adrenergic receptors (beta 2-AR). Activation of these receptors results in an increase in intracellular levels of cyclic-AMP, potentially creating a potent inhibitor of Th cell responses. Results: For the allergic asthma model, female wildtype BALB/c mice were challenged with OVA, and exercised (13.5 m/min for 45 min) 3x/week for 4 weeks. TREG cells were isolated from all mouse asthma/exercise groups, including beta 2-AR(-/-) mice, to test suppressive function and intracellular cAMP levels. In these studies, cAMP levels were increased in TREG cells isolated from exercised mice. When beta 2-AR expression was absent on TREG cells, cAMP levels were significantly decreased. Correlatively, their suppressive function was compromised. Next, TREG cells from all mouse groups were tested for suppressive function after treatment with either a pharmaceutical beta 2-adrenergic agonist or an effector-specific cAMP analogue. These experiments showed TREG cell function was increased when treated with either a beta(2)-adrenergic agonist or effector-specific cAMP analogue. Finally, female wildtype BALB/c mice were antibody-depleted of CD25(+)CD4(+) TREG cells (anti-CD25). Twenty-four hours after TREG depletion, either beta 2-AR(-/-) or wildtype TREG cells were adoptively transferred. Recipient mice underwent the asthma/exercise protocols. beta 2-AR(-/-) TREG cells isolated from these mice showed no increase in TREG function in response to moderate aerobic exercise. Conclusion: These studies offer a novel role for beta 2-AR in regulating cAMP intracellular levels that can modify suppressive function in TREG cells.