Abstract
Therapeutic adoptive transfer of natural regulatory T cells (nTreg, CD4+ CD25+ Foxp3+ T cells) or in vivo selective expansion of nTreg cells has been demonstrated to improve the cardiac function in various cardiovascular disease models. The differentiation of nTreg cells is mediated by catecholamines via β1-adrenergic receptor (β1-AR) activation. Autoantibody against β1-adrenoceptor (β1-AA) as a β1-AR agonist is closely associated with the occurrence and deterioration of cardiac dysfunction. However, whether β1-AA has any impact on nTreg cells has not been reported. The aim of the present study was intended to assess the potential impact of β1-AA on nTreg cell differentiation and explore the underlying mechanism. It was found that the expression of multiple proteins involved in nTreg cell differentiation, immunosuppressive function, and migration was up-regulated in mice after β1-AA administration, suggesting that β1-AA may promote nTreg cell activation. In vitro, β1-AA promoted nTreg cell differentiation by up-regulating mitochondrial fatty acid oxidation (FAO) in activated CD4+ T cells via AMP-activated protein kinase (AMPK) activation and mitochondrial membrane potential reduction. In addition, the AMPK agonist facilitated β1-AA-mediated FAO and nTreg cell differentiation. To further confirm the role of AMPK in β1-AA-mediated nTreg cell differentiation, β1-AA was acted on the CD4+ T cells isolated from AMPK-deficient (AMPK−/−) mice. The result showed that the effect of β1-AA on nTreg cell differentiation was attenuated markedly after AMPK knockout. In conclusion, AMPK-mediated metabolic regulation targeting for nTreg cell restoration may be a promising therapeutic target for β1-AA-positive patients with cardiac dysfunction.
Highlights
CD4+ T cells are known as the most important participant in adaptive immunity of the organism
Autoantibody targeting the second extracellular loop of β1-adrenoceptor (β1-AA) is commonly detected in circulating blood of the patients with cardiac dysfunction caused by etiologies like dilated cardiomyopathy, ischemic heart disease, and arrhythmia9–11. β1-AA was found to exhibit the agonist-like effects on β1-adrenergic receptor (β1-AR), such as increasing the intracellular calcium level promoting the beating frequency of neonatal rat cardiomyocytes and inducing cAMP production[12,13,14]
Activation of circulating nTreg cells in mice was promoted by β1-AA After 8 weeks β1-AR monoclonal antibody (β1-AR mAb) administration, optical density (OD) value of serum β1AA was increased in mice, indicating that β1-AA-positive model was created successfully (Supplemental Fig. 1)
Summary
CD4+ T cells are known as the most important participant in adaptive immunity of the organism. LVEF of the cardiac dysfunction patients improved obviously after removing β1-AA by immunoadsorption (IA) treatment[16]. It is not elucidated about the underlying mechanism related to β1-AA-induced cardiac dysfunction. Our previous and other studies found that in β1-AA-positive murine, the cardiac function was decreased but accompanied by an increase in the peripheral CD4+/ CD8+ T cell ratio; in addition, part of the myocardium was infiltrated by large number of T cells[17]. Accompanied by cardiac function improvement of the β1-AA-positive cardiac dysfunction after IA treatment, the number of circulating nTreg cells increased significantly[18,19]. Whether β1-AA as a agonist-like substance of β1-AR can exert a direct effect on nTreg cells has not been reported
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