Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Cell, 2018-12, Vol.175 (7), p.1780-1795.e19

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •T cells utilize GLS to support glutaminolysis that integrates with glycolysis•GLS promotes differentiation and function of Th17 cells yet restrains Th1 cells•GLS alters chromatin and gene expression to enhance IL2 and mTORC1 signaling•Targeting GLS protects from Th17 and enhances Th1 cells but can lead to exhaustion Glutamine metabolism, and its effects on chromatin, promotes Th17 but constrains Th1 and CTL effector cell differentiation.