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

By Marc O. Johnson, Melissa M. Wolf, M. Madden, G. Andrejeva, Ayaka Sugiura, Diana C. Contreras, Damian Maseda, Maria Liberti, Katelyn Paz, Rigel J. Kishton and 13 more. Cell, 2018

636 citations recorded by the source corpus.

SUMMARY 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.

Subfields: Cancer Research, Immunology

View Paper: https://www.semanticscholar.org/paper/344dad68bc858b7f85e6f30dc44d50035144f95b

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In Cancer Research

1. S. Grivennikov
2. F. Greten
3. J. Rathmell
4. M. Karin

In Immunology

1. S. Grivennikov
2. F. Greten
3. J. Rathmell
4. M. Karin

Citations in the corpus

• Targeting Metabolism to Improve the Tumor Microenvironment for Cancer Immunotherapy. (2020, methodology): “While Th17 cells remain dependent on GLS and were suppressed by GLS inhibition or genetic deletion, Th1 and cytotoxic T cells adapted to become GLS-independent through upregulation of glycolysis (Araujo, Khim, Mkhikian, Mortales, & Demetriou, 2017; Johnson et al., 2018; Kono et al., 2019).”
• Inflammation and Cancer: Triggers, Mechanisms and Consequences (2019, background): “, 2018) and similar processes can be enforced by regulatory T cells and by metabolic products of TME, such as hypoxia, glutamine or potassium ions (Clever et al., 2016; Eil et al., 2016; Johnson et al., 2018).”