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

• Published in: The Journal of biological chemistry 2015-12, Vol.290 (49), p.29329-29344
• Main Authors: Chien, Ming-Wei, Lin, Ming-Hong, Huang, Shing-Hwa, Fu, Shin-Huei, Hsu, Chao-Yuan, Yen, B. Lin-Ju, Chen, Jiann-Torng, Chang, Deh-Ming, Sytwu, Huey-Kang
• Format: Article
• Language: English
• Subjects: Animals; autoimmune disease; Autoimmune Diseases - metabolism; CD25; CD4-Positive T-Lymphocytes - cytology; Cell Differentiation; cytokine; diabetes; Down-Regulation; Female; Glucosamine; Glucosamine - chemistry; Glucose Transporter Type 1 - metabolism; Glycosylation; Immunology; Interleukin-2 Receptor alpha Subunit - metabolism; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Mice, Transgenic; multiple sclerosis; N-linked glycosylation; Signal Transduction; T helper cells; Th1 Cells - cytology; Th17 Cells - cytology; Th2 Cells - cytology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.674671

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. 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.