Glucosamine Modulates T Cell Differentiation through Down-regulating N-Linked Glycosylation of CD25

Ming-Wei Chien; Ming-Hong Lin; Shing-Hwa Huang; Shin-Huei Fu; Chao-Yuan Hsu; B. Lin-Ju Yen; Jiann-Torng Chen; Deh-Ming Chang; Huey-Kang Sytwu

doi:10.1074/jbc.M115.674671

Glucosamine Modulates T Cell Differentiation through Down-regulating N-Linked Glycosylation of CD25*

From the ^‡Graduate Institute of Life Sciences,
^§Department and Graduate Institute of Microbiology and Immunology,
^¶Department of Biology and Anatomy and Surgery,
^**Department of Ophthalmology, Tri-Service General Hospital,
^‡‡Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, 11490 Taiwan and
^‖Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, 35053 Taiwan

↵1 To whom correspondence should be addressed: Dept. and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, 161, Section 6, Min-Chuan East Road, Neihu, Taipei. Tel.: (886)-2-87923100 *18539; Fax: (886)-2-87921774; E-mail: sytwu{at}ndmctsgh.edu.tw.

Background: Glucosamine is an amino sugar that has immunoregulatory effects on T cell-mediated diseases.

Results: Glucosamine inhibits Th1, Th2, iTreg cells, but promotes Th17 cell development through interference with N-glycosylation of CD25.

Conclusion: Glucosamine modulates T cell differentiation in vivo and subsequently influences the progression and severity of autoimmune diseases.

Significance: Glucosamine-mediated modulation of CD25 glycosylation can be beneficial to controlling autoimmune diseases.

Abstract

Glucosamine has immunomodulatory effects on autoimmune diseases. However, the mechanism(s) through which glucosamine modulates different T cell subsets and diseases remain unclear. We demonstrate that glucosamine impedes Th1, Th2, and iTreg but promotes Th17 differentiation through down-regulating N-linked glycosylation of CD25 and subsequently inhibiting its downstream Stat5 signaling in a dose-dependent manner. The effect of glucosamine on T helper cell differentiation was similar to that induced by anti-IL-2 treatment, further supporting an IL-2 signaling-dependent modulation. Interestingly, excess glucose rescued this glucosamine-mediated regulation, suggesting a functional competition between glucose and glucosamine. High-dose glucosamine significantly decreased Glut1 N-glycosylation in Th1-polarized cells. This finding suggests that both down-regulated IL-2 signaling and Glut1-dependent glycolytic metabolism contribute to the inhibition of Th1 differentiation by glucosamine. Finally, glucosamine treatment inhibited Th1 cells in vivo, prolonged the survival of islet grafts in diabetic recipients, and exacerbated the severity of EAE. Taken together, our results indicate that glucosamine interferes with N-glycosylation of CD25, and thereby attenuates IL-2 downstream signaling. These effects suggest that glucosamine may be an important modulator of T cell differentiation and immune homeostasis.

Footnotes

↵* This work was supported by the Ministry of Science and Technology, ROC (MOST 103-2321-B-016-001, MOST 103-2320-B-016-017-MY3, MOST 104-2320-B-016-014-MY3), Tri-Service General Hospital (TSGH-C103-005-007-009-S01, TSGH-C104-008-S02), and in part by the C. Y. Foundation for Advancement of Education, Sciences. and Medicine. The authors declare that they have no conflicts of interest with the contents of this article.