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bioRxiv · 10.1101/287920

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

Gabrysova, L.·Mann, E. H.·Bradley, L.·MacRae, J. I.·Whicher, C.·Hawrylowicz, C. M.·Anastasiou, D.·O'Garra, A.
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Abstract

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-2R 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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Gabrysova, L., Mann, E. H., Bradley, L., MacRae, J. I., Whicher, C., Hawrylowicz, C. M., Anastasiou, D., O'Garra, A.. 2018-03-23. Glycosylation-dependent modulation of the lL-2 signaling axis determines Th17 differentiation and IL-10 production. https://doi.org/10.1101/287920

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