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

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.