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 ß2-adrenergic receptors (ß2-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) 3×/week for 4 weeks. TREG cells were isolated from all mouse asthma/exercise groups, including ß2-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 ß2-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 ß2-adrenergic agonist or an effector-specific cAMP analogue. These experiments showed TREG cell function was increased when treated with either a ß2-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 ß2-AR-/- or wildtype TREG cells were adoptively transferred. Recipient mice underwent the asthma/exercise protocols. ß2-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 ß2-AR in regulating cAMP intracellular levels that can modify suppressive function in TREG cells.

Moderate aerobic exercise alters migration patterns of antigen specific T helper cells within an asthmatic lung.

Studies have indicated increased incidence and severity of allergic asthma due to western lifestyle and increased sedentary activity. Investigations also indicate that exercise reduces the severity of asthma; however, a mechanism of action has not been elucidated. Additional work implicates re-distribution of T helper (Th) cells in mediating alterations of the immune system as a result of moderate aerobic exercise in vivo. We have previously reported that exercise decreases T helper 2 (Th2) responses within the lungs of an ovalbumin (OVA)-sensitized murine allergic asthma model. Therefore, we hypothesized that exercise alters the migration of OVA-specific Th cells in an OVA-challenged lung. To test this hypothesis, wildtype mice received OVA-specific Th cells expressing a luciferase-reporter construct and were OVA-sensitized and exercised. OVA-specific Th cell migration was decreased in OVA-challenged lungs of exercised mice when compared to their sedentary controls. Surface expression levels of lung-homing chemokine receptors, CCR4 and CCR8, on Th cells and their cognate lung-homing chemokine gradients revealed no difference between exercised and sedentary OVA-sensitized mice. However, transwell migration experiments demonstrated that lung-derived Th cells from exercised OVA-sensitized mice exhibited decreased migratory function versus controls. These data suggest that Th cells from exercised mice are less responsive to lung-homing chemokine. Together, these studies demonstrate that moderate aerobic exercise training can reduce the accumulation of antigen-specific Th cell migration into an asthmatic lung by decreasing chemokine receptor function.