Targeting T cell activation and lupus autoimmune phenotypes by inhibiting glucose transporters

Wei Li, Ganlin Qu, Seung Chul Choi, Caleb Cornaby, Anton Titov, Natalie Kanda, Xiangyu Teng, Haiting Wang, Laurence Morel

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

CD4+ T cells have numerous features of over-activated cellular metabolism in lupus patients and mouse models of the disease. This includes a higher glycolysis than in healthy controls. Glucose transporters play an essential role in glucose metabolism by controlling glucose import into the cell from the extracellular environment. We have previously shown that treatment of lupus-prone mice with 2-deoxy-D-glucose, which inhibits the first step of glycolysis was sufficient to prevent autoimmune activation. However, direct targeting of glucose transporters has never been tested in a mouse model of lupus. Here, we show that CG-5, a novel glucose transporter inhibitor, ameliorated autoimmune phenotypes in a spontaneous lupus-prone mouse model, B6.NZM2410.Sle1.Sle2.Sle3 (Triple-congenic, TC), and in a chronic graft- vs. host-disease (cGVHD) model of induced lupus. In vitro, CG-5 blocked glycolysis in CD4+ T cells, and limited the expansion of CD4+ T cells induced by alloreactive stimulation. CG-5 also modulated CD4+ T cell polarization by inhibiting Th1 and Th17 differentiation and promoting regulatory T (Treg) induction. Moreover, CG-5 treatment reduced lupus phenotypes including the expansion of germinal center B (GC B) cells, as well as the production of autoantibodies in both TC mice and cGVHD models. Finally, CG-5 blocked glycolysis in human T cells. Overall, our data suggest that blocking glucose uptake with a small molecule inhibitor ameliorates autoimmune activation, at least partially due to its inhibition of glycolysis in CD4+ T cells.

Original languageEnglish (US)
Article number833
JournalFrontiers in immunology
Volume10
Issue numberMAR
DOIs
StatePublished - 2019
Externally publishedYes

Keywords

  • Glucose transporter
  • Glycolysis
  • Metabolism
  • Systemic lupus erythematosus
  • T cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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