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Glycosylation-dependent modulation of the lL-2 signaling axis determines Th17 differentiation and IL-10 production

View ORCID ProfileLeona Gabryšová, Elizabeth H. Mann, Lydia Bradley, James I. MacRae, Charlotte Whicher, Catherine M. Hawrylowicz, Dimitrios Anastasiou, Anne O’Garra
doi: https://doi.org/10.1101/287920
Leona Gabryšová
1Immunoregulation and Infection Laboratory, The Francis Crick Institute, London NW1 1AT, UK
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  • ORCID record for Leona Gabryšová
  • For correspondence: Leona.Gabrysova@crick.ac.uk
Elizabeth H. Mann
1Immunoregulation and Infection Laboratory, The Francis Crick Institute, London NW1 1AT, UK
2MRC and Asthma-UK Centre for Allergic Mechanisms in Asthma, King’s College London, London SE1 9RT, UK
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Lydia Bradley
1Immunoregulation and Infection Laboratory, The Francis Crick Institute, London NW1 1AT, UK
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James I. MacRae
3Metabolomics Science Technology Platform, The Francis Crick Institute, London NW1 1AT, UK
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Charlotte Whicher
1Immunoregulation and Infection Laboratory, The Francis Crick Institute, London NW1 1AT, UK
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Catherine M. Hawrylowicz
2MRC and Asthma-UK Centre for Allergic Mechanisms in Asthma, King’s College London, London SE1 9RT, UK
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Dimitrios Anastasiou
4Cancer Metabolism Laboratory, The Francis Crick Institute, London NW1 1AT, UK
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Anne O’Garra
1Immunoregulation and Infection Laboratory, The Francis Crick Institute, London NW1 1AT, UK
5National Heart and Lung Institute, Faculty of Medicine, Imperial College London SW3 6LY, London, UK
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SUMMARY

Metabolism plays an essential role in shaping T helper (Th) cell responses including the production of pro-inflammatory cytokines, however the effects on IL-10 have not been investigated. We show that the glucose analogue 2-deoxyglucose (2DG) specifically inhibits Th1 and Th2 cell differentiation and accompanying IL-10 production. In contrast, 2DG promotes IL-17A production by Th17 cells, even in the presence of IL-2 known to limit Th17 differentiation, whilst totally abrogating the production of IL-10. Notably, rather than inhibiting glycolysis, 2DG acts through the inhibition of glycosylation, which is critical for IL-2Rα surface expression and downstream signaling in both mouse and man. Strikingly, IL-2 is essential for IL-10 production by Th17 cells, in contrast to its inhibitory effect on the production of IL-17A. Our study reveals a previously unappreciated, anti-inflammatory role for IL-2 in Th17 cell production of IL-10 and thus identifies a novel mechanism to limit Th17 pathogenicity.

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Posted March 23, 2018.
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Glycosylation-dependent modulation of the lL-2 signaling axis determines Th17 differentiation and IL-10 production
Leona Gabryšová, Elizabeth H. Mann, Lydia Bradley, James I. MacRae, Charlotte Whicher, Catherine M. Hawrylowicz, Dimitrios Anastasiou, Anne O’Garra
bioRxiv 287920; doi: https://doi.org/10.1101/287920
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Glycosylation-dependent modulation of the lL-2 signaling axis determines Th17 differentiation and IL-10 production
Leona Gabryšová, Elizabeth H. Mann, Lydia Bradley, James I. MacRae, Charlotte Whicher, Catherine M. Hawrylowicz, Dimitrios Anastasiou, Anne O’Garra
bioRxiv 287920; doi: https://doi.org/10.1101/287920

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