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