PRKAG2.2 is essential for FoxA1⁺ regulatory T cell differentiation and metabolic rewiring distinct from FoxP3⁺...

Forkhead box A1 (FoxA1)⁺ regulatory T cells (T_regs) exhibit distinct characteristics from FoxP3⁺ T_regs while equally effective in exerting anti-inflammatory properties. The role of FoxP3⁺ T_regs in vivo has been challenged, motivating a better understanding of other T_regs in modulating hyperactive immune responses. FoxA1⁺ T_regs are generated on activation of the transcription factor FoxA1 by interferon-β (IFNβ), an anti-inflammatory cytokine. T cell activation, expansion, and function hinge on metabolic adaptability. We demonstrated that IFNβ promotes a metabolic rearrangement of FoxA1⁺ T_regs by enhancing oxidative phosphorylation and mitochondria clearance by mitophagy. In response to IFNβ, FoxA1 induces a specific transcription variant of adenosine 5'-monophosphate-activated protein kinase (AMPK) γ2 subunit, PRKAG2.2. This leads to the activation of AMPK signaling, thereby enhancing mitochondrial respiration and mitophagy by ULK1-BNIP3. This IFNβ-FoxA1-PRKAG2.2-BNIP3 axis is pivotal for their suppressive function. The involvement of PRKAG2.2 in FoxA1⁺ T_reg, not FoxP3⁺ T_reg differentiation, underscores the metabolic differences between T_reg populations and suggests potential therapeutic targets for autoimmune diseases.