O-GlcNAcylation and low glycolysis underpin Th2 polarization by dendritic cells
Pelgrom, L. R.; Quik, M.; Fernandez, J. J.; Patente, T. A.; Heieis, G.; Sergushichev, A. A.; Kang, J.; Wang, X.; Dontaine, J.; Fabre, M.-S.; Otto, F.; van der Ham, A. J.; Bloemberg, L.; Koenig, M.; Winkel, B. M. F.; Tjokrodirijo, R. T. N.; De Ru, A. H.; Maizels, R.; Roestenberg, M.; Xia, T.; Shi, Y.; Lamiable, O.; Bertrand, L.; van Veelen, P. A.; Artyomov, M. N.; Hokke, C. H.; Everts, B.
Show abstract
Activation of dendritic cells (DCs) is dependent on rewiring of their cellular metabolism. However, the metabolic requirements for DCs to prime T helper 2 (Th2) responses are still poorly understood. Using unbiased transcriptomics and non-targeted metabolomics we find that helminth antigen-conditioned human DCs suppress glycolysis while increasing hexosamine biosynthesis to fuel protein O-GlcNAcylation. Functionally, glycolytic inhibition of DCs selectively enhanced, while blocking O-GlcNAcylation impaired, Th2-priming capacity. In helminth infection and allergic challenge, Th2 responses were also attenuated in vivo in mice with specific deletion of O-GlcNAc Transferase (OGT) in CD11c-expressing cells. Mechanistically, through proteomic analysis and functional validation, we identified O-GlcNAcylation as a critical negative regulator of immune synapse formation by controlling cytoskeletal organization via Fascin-1 and Zyxin, thereby dampening TCR signalling to promote Th2 polarization. Altogether we reveal a novel metabolic program in DCs that governs Th2 polarization, that could potentially be harnessed to treat type 2 mediated inflammatory diseases.
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