Autoantibody against β1-adrenoceptor promotes the differentiation of natural regulatory T cells from activated CD4+ T cells by up-regulating AMPK-mediated fatty acid oxidation.

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.

journal_name

Cell Death Dis

journal_title

Cell death & disease

authors

Xu W,Wu Y,Wang L,Bai Y,Du Y,Li Y,Cao N,Zhao Y,Zhang Y,Liu H

doi

10.1038/s41419-018-1209-2

subject

Has Abstract

pub_date

2019-02-15 00:00:00

pages

158

issue

3

issn

2041-4889

pii

10.1038/s41419-018-1209-2

journal_volume

10

pub_type

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