PPAR-γ regulates the effector function of human T helper 9 cells by promoting glycolysis

Nicole L. Bertschi, Oliver Steck, Fabian Luther, Cecilia Bazzini, Leonhard Meyenn, Stefanie Schärli, Angela Vallone, Andrea Felser, Irene Keller, Olivier Friedli, Stefan Freigang, Nadja Begré, Susanne Radonjic-Hoesli, Cristina Lamos, Max Philip Gabutti, Michael Benzaquen, Markus Laimer, Dagmar Simon, Jean-Marc Nuoffer and Christoph Schlapbach ()
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Nicole L. Bertschi: Bern University Hospital, University of Bern
Oliver Steck: Bern University Hospital, University of Bern
Fabian Luther: Bern University Hospital, University of Bern
Cecilia Bazzini: Bern University Hospital, University of Bern
Leonhard Meyenn: Bern University Hospital, University of Bern
Stefanie Schärli: Bern University Hospital, University of Bern
Angela Vallone: Bern University Hospital, University of Bern
Andrea Felser: University of Bern
Irene Keller: University of Bern
Olivier Friedli: University of Bern
Stefan Freigang: University of Bern
Nadja Begré: Bern University Hospital, University of Bern
Susanne Radonjic-Hoesli: Bern University Hospital, University of Bern
Cristina Lamos: Bern University Hospital, University of Bern
Max Philip Gabutti: Bern University Hospital, University of Bern
Michael Benzaquen: Bern University Hospital, University of Bern
Markus Laimer: Bern University Hospital, University of Bern
Dagmar Simon: Bern University Hospital, University of Bern
Jean-Marc Nuoffer: University of Bern
Christoph Schlapbach: Bern University Hospital, University of Bern

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract T helper 9 (TH9) cells promote allergic tissue inflammation and express the type 2 cytokines, IL-9 and IL-13, as well as the transcription factor, PPAR-γ. However, the functional role of PPAR-γ in human TH9 cells remains unknown. Here, we demonstrate that PPAR-γ drives activation-induced glycolysis, which, in turn, promotes the expression of IL-9, but not IL-13, in an mTORC1-dependent manner. In vitro and ex vivo experiments show that the PPAR-γ-mTORC1-IL-9 pathway is active in TH9 cells in human skin inflammation. Additionally, we find dynamic regulation of tissue glucose levels in acute allergic skin inflammation, suggesting that in situ glucose availability is linked to distinct immunological functions in vivo. Furthermore, paracrine IL-9 induces expression of the lactate transporter, MCT1, in TH cells and promotes their aerobic glycolysis and proliferative capacity. Altogether, our findings uncover a hitherto unknown relationship between PPAR-γ-dependent glucose metabolism and pathogenic effector functions in human TH9 cells.

Date: 2023
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DOI: 10.1038/s41467-023-38233-x

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