Journal Article

Transcriptional factor ICER promotes glutaminolysis and the generation of Th17 cells

Maeda, Kayaho, Tsokos, George C., Kono, Michihito, Yoshida, Nobuya

2018

Overview

SignificanceTh17 cells unlike other CD4+ T helper subsets use glutaminolysis as a source of energy and upregulate Gls1. Inhibition of Gls1 ameliorates Th17 differentiation in vitro and experimental autoimmune encephalomyelitis in mice. Mechanistically this is accomplished through the upregulation of Gls1 by the Th17-promoting transcription factor, inducible cAMP early repressor (ICER). These findings claim an essential role of glutaminolysis in the generation of Th17 cells and offer an approach to control diseases linked to their generation. Glutaminolysis is a well-known source of energy for effector T cells but its contribution to each T cell subset and the mechanisms which are responsible for the control of involved metabolic enzymes are not fully understood. We report that Th17 but not Th1, Th2, or Treg cell induction in vitro depends on glutaminolysis and the up-regulation of glutaminase 1 (Gls1), the first enzyme in the glutaminolysis pathway. Both pharmacological and siRNA-based selective inhibition of Gls1 reduced in vitro Th17 differentiation and reduced the CD3/TCR-mediated increase of the mammalian target of rapamycin complex 1 activity. Treatment of mice with a Gls1 inhibitor ameliorated experimental autoimmune encephalomyelitis. Furthermore, RAG1-deficient mice that received Gls1-shRNA–transfected 2D2 T cells had reduced experimental autoimmune encephalomyelitis scores compared with those that received control-shRNA–treated cells. Next we found that T cells deficient in inducible cAMP early repressor (ICER), a transcriptional factor known to promote Th17 differentiation, display reduced activity of oxidative phosphorylation rates in the presence of glutamine and reduced Gls1 expression, both of which could be restored by ICER overexpression. Finally, we demonstrate that ICER binds to the gls1 promoter directly and increases its activity. These findings demonstrate the importance of glutaminolysis in the generation of Th17 and the direct control of Gls1 activity by the IL-17–promoting transcription factor ICER. Pharmaceutical modulation of the glutaminolysis pathway should be considered to control Th17-mediated pathology.

• Publisher: National Academy of Sciences
• Subject: Animals / Autoimmune diseases / Autoimmunity / Biological Sciences / CD3 antigen / Cells / Cyclic AMP Response Element Modulator - genetics / Cyclic AMP Response Element Modulator - metabolism / Differentiation / Effector cells / Encephalomyelitis, Autoimmune, Experimental - immunology / Experimental allergic encephalomyelitis / Glutaminase / Glutaminase - antagonists & inhibitors / Glutaminase - metabolism / Glutamine / Glutamine - metabolism / Helper cells / Interleukin 17 / Lymphocytes / Lymphocytes T / Medical Sciences / Mice / Mice, Transgenic / Oxidative phosphorylation / Pathology / Pharmacology / Phosphorylation / RAG1 protein / Rapamycin / siRNA / Studies / T cell receptors / Th17 Cells - cytology / Th17 Cells - immunology / Th17 Cells - metabolism / TOR protein