Age-associated impairment of T cell immunity is linked to sex-dimorphic elevation of N-glycan branching

Mkhikian, Haik; Hayama, Ken; Khachikyan, Khachik; Li, Carey; Zhou, Raymond; Pawling, Judy; Klaus, Suzi; Tran, Phuong Q. N.; Ly, Kim M.; Gong, Andrew D.; Saryan, Hayk; Hai, Jasper L.; Grigoryan, David; Lee, Philip L.; Newton, Barbara L.; Raffatellu, Manuela; Dennis, James W.; Demetriou, Michael

doi:10.1038/s43587-022-00187-y

Cited by 13 publications

(11 citation statements)

References 60 publications

(121 reference statements)

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“…Whereas the above findings suggest that enhancing flux through the salvage HBP may mitigate autoimmunity, its benefit may be limited in other cases. For example, naïve T cells of aging mice have particularly increased N -glycan branching, which is associated with impaired immunity [ 237 ]. Furthermore, the levels of serum GlcNAc increase with age, and serum GlcNAc synergizes with IL-7 signaling to elevate N -glycan branching in human T cells.…”

Section: Hbp In Health and Diseasementioning

confidence: 99%

The Hexosamine Biosynthesis Pathway: Regulation and Function

Paneque

Fortus

Zheng

et al. 2023

Genes

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The hexosamine biosynthesis pathway (HBP) produces uridine diphosphate-N-acetyl glucosamine, UDP-GlcNAc, which is a key metabolite that is used for N- or O-linked glycosylation, a co- or post-translational modification, respectively, that modulates protein activity and expression. The production of hexosamines can occur via de novo or salvage mechanisms that are catalyzed by metabolic enzymes. Nutrients including glutamine, glucose, acetyl-CoA, and UTP are utilized by the HBP. Together with availability of these nutrients, signaling molecules that respond to environmental signals, such as mTOR, AMPK, and stress-regulated transcription factors, modulate the HBP. This review discusses the regulation of GFAT, the key enzyme of the de novo HBP, as well as other metabolic enzymes that catalyze the reactions to produce UDP-GlcNAc. We also examine the contribution of the salvage mechanisms in the HBP and how dietary supplementation of the salvage metabolites glucosamine and N-acetylglucosamine could reprogram metabolism and have therapeutic potential. We elaborate on how UDP-GlcNAc is utilized for N-glycosylation of membrane and secretory proteins and how the HBP is reprogrammed during nutrient fluctuations to maintain proteostasis. We also consider how O-GlcNAcylation is coupled to nutrient availability and how this modification modulates cell signaling. We summarize how deregulation of protein N-glycosylation and O-GlcNAcylation can lead to diseases including cancer, diabetes, immunodeficiencies, and congenital disorders of glycosylation. We review the current pharmacological strategies to inhibit GFAT and other enzymes involved in the HBP or glycosylation and how engineered prodrugs could have better therapeutic efficacy for the treatment of diseases related to HBP deregulation.

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Section: Hbp In Health and Diseasementioning

confidence: 99%

The Hexosamine Biosynthesis Pathway: Regulation and Function

Paneque

Fortus

Zheng

et al. 2023

Genes

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“…This sexual-dimorphic branching pattern has been attributed to elevated IL-7 signaling by naïve T cells from aged females, resulting in higher phosphorylation of the transcription factor STAT5 [68] . Genetic deletion of Mgat2 enhanced TCR signaling and reactivity of old-female CD4 + T cells and Mgat2-deficient T cells exhibited greater capacity to eliminate salmonella infection due to greater T H 17 differentiation when compared to wild-type CD4 + T cells from old females [68] .…”

Section: Mgat2 (Gnt-ii)mentioning

confidence: 99%

“…Sex differences in N -linked glycan branching have been reported in both aged mice and humans. Naïve CD4 + T cells from old females exhibited elevated basal levels of N -linked glycan branching, which was associated with reduced reactivity and proinflammatory cues when compared to either memory or old-male naïve CD4 + T cells [68] . This sexual-dimorphic branching pattern has been attributed to elevated IL-7 signaling by naïve T cells from aged females, resulting in higher phosphorylation of the transcription factor STAT5 [68] .…”

Section: N-acetylglucosaminyltranferases (Gnts/mgats)mentioning

confidence: 99%

N-linked glycans: an underappreciated key determinant of T cell development, activation, and function

Abdelbary,

Nolz

2023

Immunometabolism

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N-linked glycosylation is a post-translational modification that results in the decoration of newly synthesized proteins with diverse types of oligosaccharides that originate from the amide group of the amino acid asparagine. The sequential and collective action of multiple glycosidases and glycosyltransferases are responsible for determining the overall size, composition, and location of N-linked glycans that become covalently linked to an asparagine during and after protein translation. A growing body of evidence supports the critical role of N-linked glycan synthesis in regulating many features of T cell biology, including thymocyte development and tolerance, as well as T cell activation and differentiation. Here, we provide an overview of how specific glycosidases and glycosyltransferases contribute to the generation of different types of N-linked glycans and how these post-translational modifications ultimately regulate multiple facets of T cell biology.

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“…For analysis of CD73 and CD39 expression in young and healthy C57Bl/6 mice, raw-count RNA sequencing gene expression data of bulk CD19+ thymic B cells (GEO: GSE107110) [15], purified CD4+ naive T cells (CD3+CD4+CD25-CD62L+CD44−), and effector memory (CD3+CD4+CD25-CD62L-CD44+) T cells (GEO: GSE184496) [16] were retrieved from the Gene Expression Omnibus (GEO) portal. Gene expression was computed using the log2-transformed TPM (transcripts per million) method.…”

Section: Genomic and Transcriptomic Analysesmentioning

confidence: 99%

CD73 Promotes Chronic Lymphocytic Leukemia

Allard

Chrobák

Barèche

et al. 2022

Cancers

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The ecto-nucleotidase CD73 is an important immune checkpoint in tumor immunity that cooperates with CD39 to hydrolyze pro-inflammatory extracellular ATP into immunosuppressive adenosine. While the role of CD73 in immune evasion of solid cancers is well established, its role in leukemia remains unclear. To investigate the role of CD73 in the pathogenesis of chronic lymphocytic leukemia (CLL), Eµ-TCL1 transgenic mice that spontaneously develop CLL were crossed with CD73−/− mice. Disease progression in peripheral blood and spleen, and CLL markers were evaluated by flow cytometry and survival was compared to CD73-proficient Eµ-TCL1 transgenic mice. We observed that CD73 deficiency significantly delayed CLL progression and prolonged survival in Eµ-TCL1 transgenic mice, and was associated with increased accumulation of IFN-γ+ T cells and effector-memory CD8+ T cells. Neutralizing IFN-γ abrogated the survival advantage of CD73-deficient Eµ-TCL1 mice. Intriguingly, the beneficial effects of CD73 deletion were restricted to male mice. In females, CD73 deficiency was uniquely associated with the upregulation of CD39 in normal lymphocytes and sustained high PD-L1 expression on CLL cells. In vitro studies revealed that adenosine signaling via the A2a receptor enhanced PD-L1 expression on Eµ-TCL1-derived CLL cells, and a genomic analysis of human CLL samples found that PD-L1 correlated with adenosine signaling. Our study, thus, identified CD73 as a pro-leukemic immune checkpoint in CLL and uncovered a previously unknown sex bias for the CD73-adenosine pathway.

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Age-associated impairment of T cell immunity is linked to sex-dimorphic elevation of N-glycan branching

Cited by 13 publications

References 60 publications

The Hexosamine Biosynthesis Pathway: Regulation and Function

The Hexosamine Biosynthesis Pathway: Regulation and Function

N-linked glycans: an underappreciated key determinant of T cell development, activation, and function

CD73 Promotes Chronic Lymphocytic Leukemia

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