Autoantibody against β(1)-adrenoceptor promotes the differentiation of natural regulatory T cells from activated CD4(+) T cells by up-regulating AMPK-mediated fatty acid oxidation

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 β(1)-adrenergic receptor (β(1)-AR) activation. Autoantibody against β(1)-adrenoceptor (β(1)-AA) as a β(1)-AR agonist is closely associated with the occurrence and deterioration of cardiac dysfunction. However, whether β(1)-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 β(1)-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 β(1)-AA administration, suggesting that β(1)-AA may promote nTreg cell activation. In vitro, β(1)-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 β(1)-AA-mediated FAO and nTreg cell differentiation. To further confirm the role of AMPK in β(1)-AA-mediated nTreg cell differentiation, β(1)-AA was acted on the CD4(+) T cells isolated from AMPK-deficient (AMPK(−/−)) mice. The result showed that the effect of β(1)-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 β(1)-AA-positive patients with cardiac dysfunction.