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

Chien, Ming-Wei; Lin, Ming‐Hong; Huang, Shing-Hwa; Hsu, Chao-Yuan; Yen, B. Linju; Chen, Jiann‐Torng; Chang, Deh‐Ming; Sytwu, Huey‐Kang

doi:10.1074/jbc.m115.674671

Cited by 39 publications

(38 citation statements)

References 60 publications

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“…N‐glycan branching on T cells has been implicated in the development of type 1 diabetes, and N‐glycan branching on glucose transporter has been implicated in the development of type 2 diabetes . Both discoveries include N‐glycan interactions with lectins, which are disrupted upon inhibition of the proper protein N‐glycosylation.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, it has been shown that it is possible to distinguish individuals with different types of diabetes based on their N-glycome data, as it is the case for the HNF1A-MODY and its differentiation from other common and rare types of diabetes [38,42]. N-glycan branching on T cells has been implicated in the development of type 1 diabetes, and N-glycan branching on glucose transporter has been implicated in the development of type 2 diabetes [23,43,44,73,105]. Both discoveries include N-glycan interactions with lectins, which are disrupted upon inhibition of the proper protein N-glycosylation.…”

Section: Discussionmentioning

confidence: 99%

“…Oral GlcNAc supplementation in these mice enhanced T cell N-glycan branching and protected against the disease [105]. IL-2Ra (CD25) is also an N-glycoprotein involved in T cell survival and proliferation; its N-glycosylation and thus also a downstream signalling was inhibited by supplementation with glucosamine; thus, demonstrating a dual role of N-glycosylation in T cell differentiation [73]. As previously discussed, the kinetics of GNT-V and number of N-glycans on glycoproteins should be kept in mind, as switch-like sigmoidal responses are characteristic for GNT-V and glycoproteins with few N-glycans upon increase in GlcNAc [59].…”

Section: Mgat5-mediated N-glycan Branching Impacts T Cell Activationmentioning

confidence: 99%

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Altered N‐glycosylation profiles as potential biomarkers and drug targets in diabetes

2019

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N‐glycosylation is a ubiquitous protein modification, and N‐glycosylation profiles are emerging as both biomarkers and functional effectors in various types of diabetes. Genome‐wide association studies identified glycosyltransferase genes as candidate causal genes for type 1 and type 2 diabetes. Studies focused on N‐glycosylation changes in type 2 diabetes demonstrated that patients can be distinguished from healthy controls based on N‐glycome composition. In addition, individuals at an increased risk of future disease development could be identified based on N‐glycome profiles. Moreover, accumulating evidence indicates that N‐glycans have a major role in preventing the impairment of glucose‐stimulated insulin secretion by maintaining the glucose transporter in proper orientation, indicating that interindividual variation in protein N‐glycosylation might be a novel risk factor contributing to diabetes development. Defective N‐glycosylation of T cells has been implicated in type 1 diabetes pathogenesis. Furthermore, studies of N‐glycan alterations have successfully been used to identify individuals with rare types of diabetes (such as the HNF1A‐MODY), and also to evaluate functional significance of novel diabetes‐associated mutations. In conclusion, both N‐glycans and glycosyltransferases emerge as potential therapeutic targets in diabetes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Mgat5-mediated N-glycan Branching Impacts T Cell Activationmentioning

confidence: 99%

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Altered N‐glycosylation profiles as potential biomarkers and drug targets in diabetes

2019

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“…This could occur also through metabolites produced by the fungus itself during challenge, with S. cerevisiae strains behaving differently according to the different adaptation to the environment from which they were isolated. It was previously demonstrated that C. albicans can actively shift the balance of tryptophan metabolism in the host through soluble factors (48), and a recent study revealed the glucosamine modulatory properties on T cells (13). Indeed, fungus metabolites could somehow allow for the epigenetic changes that then form the basis for the training event.…”

Section: Discussionmentioning

confidence: 99%

Fungal Chitin Induces Trained Immunity in Human Monocytes during Cross-talk of the Host with Saccharomyces cerevisiae

Rizzetto

Ifrim

Moretti

et al. 2016

Journal of Biological Chemistry

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The immune system is essential to maintain the mutualistic homeostatic interaction between the host and its micro-and mycobiota. Living as a commensal, Saccharomyces cerevisiae could potentially shape the immune response in a significant way. We observed that S. cerevisiae cells induce trained immunity in monocytes in a strain-dependent manner through enhanced TNF␣ and IL-6 production upon secondary stimulation with TLR ligands, as well as bacterial and fungal commensals. Differential chitin content accounts for the differences in training properties observed among strains, driving induction of trained immunity by increasing cytokine production and direct antimicrobial activity both in vitro and in vivo. These chitin-induced protective properties are intimately associated with its internalization, identifying a critical role of phagosome acidification to facilitate microbial digestion. This study reveals how commensal and passenger microorganisms could be important in promoting health and preventing mucosal diseases by modulating host defense toward pathogens and thus influencing the host microbiota-immune system interactions.

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“…Other intrinsic factors including signaling molecules and miRNA have been shown to control signaling in model systems [10, 11]. Extrinsically, metabolic factors and secreted receptors [12–14] regulate IL-2R signaling in other disease settings. In this study, we examine IL-2 responsiveness in 98 T1D subjects and 95 healthy controls and explore underlying mechanisms in Teff Our results demonstrate that disease impacts IL-2/IL-2R signaling most prominently in the CD4 Teff compartment.…”

Section: Introductionmentioning

confidence: 99%

Attenuated IL-2R signaling in CD4 memory T cells of T1D subjects is intrinsic and dependent on activation state

Schwedhelm¹,

Thorpe²,

Murray³

et al. 2017

Clinical Immunology

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The IL-2/IL-2R pathway is implicated in type 1 diabetes (T1D). While its role in regulatory T cell (Treg) biology is well characterized, mechanisms that influence IL-2 responses in effector T cells (Teff) are less well understood. We compared IL-2 responses in 95 healthy control and 98 T1D subjects. In T1D, low IL-2 responsiveness was most pronounced in memory Teff. Unlike Treg, CD25 expression did not influence the Teff responses. Reduced IL-2 responses in memory Teff were not rescued by resting, remained lower after activation and proliferation, and were absent in type 2 diabetes. Comparing basal IL-2 responses in resting versus activated cells, memory Teff displayed lower, but more sustained, responses to IL-2 overtime. These results suggest that T1D–associated defects in the Teff compartment are due to intrinsic factors related to activation. Evaluation of both Teff and Treg IL-2R signaling defects in T1D subjects may inform selection of therapies.

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

Cited by 39 publications

References 60 publications

Altered N‐glycosylation profiles as potential biomarkers and drug targets in diabetes

Altered N‐glycosylation profiles as potential biomarkers and drug targets in diabetes

Fungal Chitin Induces Trained Immunity in Human Monocytes during Cross-talk of the Host with Saccharomyces cerevisiae

Attenuated IL-2R signaling in CD4 memory T cells of T1D subjects is intrinsic and dependent on activation state

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