Metabolic sensor AMPK licenses CD103+ dendritic cells to induce Treg responses

Patente, T.; Brombacher, E.; Heieis, G.; Pelgrom, L.; Zawistowska-Deniziak, A.; Otto, F.; Ozir-Fazalalikhan, A.; van der Ham, A.; Guigas, B.; Barbuto, J. A. M.; Everts, B.

doi:10.1101/2023.02.21.528293

bioRxiv · 10.1101/2023.02.21.528293

Metabolic sensor AMPK licenses CD103+ dendritic cells to induce Treg responses

Patente, T.·Brombacher, E.·Heieis, G.·Pelgrom, L.·Zawistowska-Deniziak, A.·Otto, F.·Ozir-Fazalalikhan, A.·van der Ham, A.·Guigas, B.·Barbuto, J. A. M.·Everts, B.

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Abstract

Dendritic cells (DCs) play a crucial role in promoting tolerance through priming of regulatory T cells (Treg). Several studies indicate DC tolerogenicity is dependent on catabolic metabolism. However, the role of AMP-activated Kinase (AMPK), a key energy and nutrient sensor driving catabolic metabolism, in this process is unclear. We found that human retinoic acid-induced tolerogenic CD103+ DCs (RA-DCs) display increased AMPK signaling. Interestingly, RA-DCs, but not vitamin-D3- or dexamethasone-induced tolerogenic DCs, required AMPK for Treg induction. Mechanistically, AMPK underpinned RA-driven tolerogenicity by promoting RALDH activity in a FoxO3-dependent manner. Correspondingly, mice deficient for AMPK in DCs (CD11c{Delta}AMPK1) harbored reduced frequencies of intestinal CD103+CD11b+ DCs with impaired RALDH activity. Importantly, upon infection with parasitic worm Schistosoma mansoni, that elicits strong Th2 and Treg responses, CD11c{Delta}AMPK1 mice showed a defect in Treg accumulation and concomitantly, displayed an impaired ability to control Type 2 immunity-driven granulomatous inflammation against the parasite eggs. Together, our findings identify AMPK as a key regulator of tolerance by CD103+ DCs. SummaryDendritic cells (DCs) are critical for inducing tolerance. However, how metabolic cues control their tolerogenicity is still poorly understood. Patente et al demonstrate that AMPK is crucial for Treg induction by retinoic acid-primed tolerogenic CD103+ DCs.

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Patente, T., Brombacher, E., Heieis, G., Pelgrom, L., Zawistowska-Deniziak, A., Otto, F., Ozir-Fazalalikhan, A., van der Ham, A., Guigas, B., Barbuto, J. A. M., Everts, B.. 2023-02-21. Metabolic sensor AMPK licenses CD103+ dendritic cells to induce Treg responses. https://doi.org/10.1101/2023.02.21.528293

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