Metabolic sensor AMPK licenses intestinal CD103⁺ DCs to induce T_reg responses

Intestinal dendritic cells (DCs) play a central role in maintaining gut tolerance through priming of peripheral regulatory T cells (pT_reg cells). DC tolerogenicity has been linked to catabolic metabolism, but the role of AMP-activated kinase (AMPK), a key regulator of catabolic metabolism, in regulating intestinal tolerance remains unclear. We found high AMPK activation in intestinal DCs, and loss of AMPKα1 in CD11c-expressing cells (CD11c^ΔAMPKα1) led to reduced frequencies of intestinal RALDH⁺ CD103⁺ cDC2s. This was associated with reduced pT_reg cell induction and consequently increased type 2 immunity in models of intestinal helminth infection. Correspondingly, CD103⁺ cDC2s from helminth-infected CD11c^ΔAMPKα1 mice failed to prime T_reg cells ex vivo. Similarly, T_reg cell induction by AMPK-deficient human retinoic acid (RA)-induced tolerogenic CD103⁺ DCs was compromised. Mechanistically, AMPK underpinned RA-driven tolerogenicity by promoting RALDH activity and TGF-β secretion in a FoxO3-dependent manner, independent from metabolic reprogramming. Our findings identify AMPK as a key regulator of intestinal DC-mediated tolerance and as a therapeutic target to counter intestinal inflammatory disease.