O‐GlcNAc Regulates CD4+ T Cell Differentiation
In: The FASEB Journal ; volume 30, issue S1 ; ISSN 0892-6638 1530-6860, 2016
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Zugriff:
In a normal immune response, antigen presenting cells (APC) engage the T cell receptor on CD4+ T cells, stimulating T cell proliferation and inducing T cell differentiation in conjunction with the cytokines secreted by APC. CD4+ T cells differentiate into effectors which secrete cytokines able to specifically neutralize different classes of pathogens. Pro‐inflammatory Th1 and Th17 effector cells are known to increase in situations of altered metabolism, such as type 1 and 2 diabetes and inflammatory bowel disease. A clear mechanism linking metabolic changes with pro‐inflammatory T cells is lacking. We hypothesize that elevated levels of O‐linked β‐N‐acetylglucosamine (O‐GlcNAc), a post‐translational modification of nuclear and cytoplasmic proteins, promotes pro‐inflammatory CD4+ differentiation. Since production of O‐GlcNAc involves input from carbohydrate, amino acid, fatty acid, and nucleic acid metabolism, the modification acts as a general sensor of a cell's nutritional status. To investigate the potential pro‐inflammatory role of O‐GlcNAc, we cultured mouse CD4+ T cells isolated from spleens with Thiamet‐G (TMG), a selective inhibitor of the enzyme that removes O‐GlcNAc (O‐GlcNAcase, OGA), before activation of the T cell receptor by plate‐bound anti‐CD3 and anti‐CD28. ELISA analysis of cytokines revealed a significant 95% increase in IL‐17A, the eponymous Th17 cytokine, in cells with TMG treatment compared to control cells that were cultured under permissive conditions in which differentiation of all effectors is equally possible. RT‐qPCR analysis showed significant increases in transcripts of IL‐17A and IFNγ, the main cytokine secreted by Th1 effectors. Taken together, these results suggest elevated O‐GlcNAc promotes the differentiation of pro‐inflammatory Th17, Th1, and/or Th1‐like Th17 cells, which are particularly pathogenic in autoimmunity. We then looked for changes in STAT3 and STAT4 activation, since these STATs are necessary for the transcription of Th17 and Th1 lineage defining programs, ...
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O‐GlcNAc Regulates CD4+ T Cell Differentiation
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Autor/in / Beteiligte Person: | Machacek, Miranda ; Slawson, Chad ; Fields, Patrick ; National Institutes of Health |
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Zeitschrift: | The FASEB Journal ; volume 30, issue S1 ; ISSN 0892-6638 1530-6860, 2016 |
Veröffentlichung: | Wiley, 2016 |
Medientyp: | academicJournal |
DOI: | 10.1096/fasebj.30.1_supplement.652.6 |
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