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Cell. 2018 Oct 30. pii: S0092-8674(18)31309-6. doi: 10.1016/j.cell.2018.10.001. [Epub ahead of print]

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

Author information

1
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
2
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
3
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
4
Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
5
Center for Cell-Based Therapy, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
6
Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
7
Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
8
Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
9
Department of Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
10
Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Center for Immunobiology, Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
11
Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Immunobiology, Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
12
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Immunobiology, Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: jeff.rathmell@vumc.org.

Abstract

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.

KEYWORDS:

T cells; chromatin; glutaminase; glutamine; mTOR; metabolism

PMID:
30392958
DOI:
10.1016/j.cell.2018.10.001

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