Activation of AMPKα1 is essential for regulatory T cell function and autoimmune liver disease prevention.

Regulatory T cells (Treg cells) are crucial for maintaining immune tolerance. Compromising the regulatory function of Treg cells can lead to autoimmune liver disease. However, how Treg cell function is regulated has not been fully clarified. Here, we report that mice with AMP-activated protein kinase alpha 1 (AMPKα1) globally knocked out spontaneously develop immune-mediated liver injury, with massive lymphocyte infiltration in the liver, elevated serum alanine aminotransferase levels, and greater production of autoantibodies. Both transplantation of wild-type bone marrow and adoptive transfer of wild-type Treg cells can prevent liver injury in AMPKα1-KO mice. In addition, Treg cell-specific AMPKα1-KO mice display histological features similar to those associated with autoimmune liver disease, greater production of autoantibodies, and hyperactivation of CD4+ T cells. AMPKα1 deficiency significantly impairs Treg cell suppressive function but does not affect Treg cell differentiation or proliferation. Furthermore, AMPK is activated upon T cell receptor (TCR) stimulation, which triggers Foxp3 phosphorylation, suppressing Foxp3 ubiquitination and proteasomal degradation. Importantly, the frequency of Treg cells and the phosphorylation levels of AMPK at T172 in circulating blood are significantly lower in patients with autoimmune liver diseases. Conclusion: Our data suggest that AMPK maintains the immunosuppressive function of Treg cells and confers protection against autoimmune liver disease.