Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism

Marc O. Johnson, Melissa M. Wolf, Matthew Z. Madden, Gabriela Andrejeva, Ayaka Sugiura, Diana C. Contreras, Damian Maseda, Maria V. Liberti, Katelyn Paz, Rigel J. Kishton, Matthew E. Johnson, Aguirre A. de Cubas, Pingsheng Wu, Gongbo Li, Yongliang Zhang, Dawn C. Newcomb, Andrew D. Wells, Nicholas P. Restifo, W. Kimryn Rathmell, Jason W. LocasaleMarco L. Davila, Bruce R. Blazar, Jeffrey C. Rathmell

Research output: Contribution to journalArticlepeer-review

285 Scopus citations


Activated T cells differentiate into functional subsets with distinct metabolic programs. Glutaminase (GLS) converts glutamine to glutamate to support the tricarboxylic acid cycle and redox and epigenetic reactions. Here, we identify a key role for GLS in T cell activation and specification. Though GLS deficiency diminished initial T cell activation and proliferation and impaired differentiation of Th17 cells, loss of GLS also increased Tbet to promote differentiation and effector function of CD4 Th1 and CD8 CTL cells. This was associated with altered chromatin accessibility and gene expression, including decreased PIK3IP1 in Th1 cells that sensitized to IL-2-mediated mTORC1 signaling. In vivo, GLS null T cells failed to drive Th17-inflammatory diseases, and Th1 cells had initially elevated function but exhausted over time. Transient GLS inhibition, however, led to increased Th1 and CTL T cell numbers. Glutamine metabolism thus has distinct roles to promote Th17 but constrain Th1 and CTL effector cell differentiation.

Original languageEnglish (US)
Pages (from-to)1780-1795.e19
Issue number7
StatePublished - Dec 13 2018

Bibliographical note

Funding Information:
We thank members of the Rathmell lab and H. Hu (University of Alabama, Birmingham) for providing MSCV-PIK3IP-IRES-Thy1.1 and control retroviral constructs, T. Dileepan and M.K. Jenkins (University of Minnesota) for providing reagents for 2W immunization and tetramer staining, and J. Cools (VIB) for providing pMx-U6 plasmids. Some CB839 for in vitro studies was generously provided by Calithera Biosciences. This research was funded by the National Institutes of Health R01 HL136664 (J.C.R.), R01 DK105550 (J.C.R.), R01 CA217987 (J.C.R., W.K.R.), R01CA193256 (J.W.L.), and P30CA01423 (J.W.L.).

Publisher Copyright:
© 2018 Elsevier Inc.


  • T cells
  • chromatin
  • glutaminase
  • glutamine
  • mTOR
  • metabolism


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