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


ABSTRACT: Forkhead box A1 (FoxA1)+ regulatory T cells (Tregs) exhibit distinct characteristics from FoxP3+ Tregs while equally effective in exerting anti-inflammatory properties. The role of FoxP3+ Tregs in vivo has been challenged, motivating a better understanding of other Tregs in modulating hyperactive immune responses. FoxA1+ Tregs 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+ Tregs 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+ Treg, not FoxP3+ Treg differentiation, underscores the metabolic differences between Treg populations and suggests potential therapeutic targets for autoimmune diseases.

SUBMITTER: Mandatori S 

PROVIDER: S-EPMC10732530 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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PRKAG2.2 is essential for FoxA1<sup>+</sup> regulatory T cell differentiation and metabolic rewiring distinct from FoxP3<sup>+</sup> regulatory T cells.

Mandatori Sara S   Liu Yawei Y   Marturia-Navarro Joana J   Hadi Mahdieh M   Henriksen Kristine K   Zheng Jin J   Rasmussen Louise Munk LM   Rizza Salvatore S   Kaestner Klaus H KH   Issazadeh-Navikas Shohreh S  

Science advances 20231220 51


Forkhead box A1 (FoxA1)<sup>+</sup> regulatory T cells (T<sub>regs</sub>) exhibit distinct characteristics from FoxP3<sup>+</sup> T<sub>regs</sub> while equally effective in exerting anti-inflammatory properties. The role of FoxP3<sup>+</sup> T<sub>regs</sub> in vivo has been challenged, motivating a better understanding of other T<sub>regs</sub> in modulating hyperactive immune responses. FoxA1<sup>+</sup> T<sub>regs</sub> are generated on activation of the transcription factor FoxA1 by interfe  ...[more]

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