Glutaminase 2 Induces Interleukin-2 Production in CD4+ T Cells by Supporting Antioxidant Defense
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Orite, Seo Yeon Kim
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CitationOrite, Seo Yeon Kim. 2019. Glutaminase 2 Induces Interleukin-2 Production in CD4+ T Cells by Supporting Antioxidant Defense. Master's thesis, Harvard Medical School.
AbstractMetabolic abnormalities of T cells contribute to pathogenesis of many autoimmune diseases, including Systemic Lupus Erythematosus (SLE). Rapidly proliferating effector T cells often utilize glutamine as an energy source to meet high energy demands. Glutaminase (Gls) is the first enzyme in the glutaminolysis pathway converting glutamine to glutamate. In addition to providing energy through glutamine processing, Gls also supports antioxidant defense against cellular stress by driving glutathione (GSH) synthesis. There are two isoforms of Gls that are differentially regulated. Gls2, but not Gls1, induced interleukin 2 (IL-2) production in CD4+ T cells of mouse and human and Jurkat cell line. Upregulation of Gls2 expression increased IL-2 production at the protein and the transcriptional levels. Moreover, Gls2 overexpression in CD4+ T cells lowered cellular oxidative stress. Taken together, I propose that Gls2 induces IL-2 production by reducing intracellular reactive oxygen species (ROS) level known to suppress IL-2 production. In addition, p53 plays an important role in this Gls2-mediated IL-2 production pathway by directly targeting the Gls2 gene. Finally, patients with SLE express reduced levels of p53 and GLS2 protein expression compared to healthy controls. These findings suggest that Gls2-mediated IL-2 induction pathway is disrupted in patients with SLE. However, further investigation is required to determine the exact molecular mechanism of this pathway and to evaluate therapeutic potential of exogenous Gls2 delivery.
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