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

被引：592

作者：

Johnson, Marc O. ^{[1
,2
]}

Wolf, Melissa M. ^{[1
]}

Madden, Matthew Z. ^{[1
]}

Andrejeva, Gabriela ^{[1
]}

Sugiura, Ayaka ^{[1
]}

Contreras, Diana C. ^{[1
]}

Maseda, Damian ^{[1
]}

Liberti, Maria V. ^{[2
]}

Paz, Katelyn ^{[3
]}

Kishton, Rigel J. ^{[4
]}

Johnson, Matthew E. ^{[5
,6
]}

de Cubas, Aguirre A. ^{[7
]}

Wu, Pingsheng ^{[8
]}

Li, Gongbo ^{[9
]}

Zhang, Yongliang ^{[9
]}

Newcomb, Dawn C. ^{[8
,10
]}

Wells, Andrew D. ^{[5
,6
]}

Restifo, Nicholas P. ^{[4
]}

Rathmell, W. Kimryn ^{[7
,10
]}

Locasale, Jason W. ^{[2
]}

Davila, Marco L. ^{[9
]}

Blazar, Bruce R. ^{[3
]}

Rathmell, Jeffrey C. ^{[1
,10
]}

机构：

[1] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN 37232 USA

[2] Duke Univ, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA

[3] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA

[4] NCI, Ctr Cell Based Therapy, NIH, Bethesda, MD 20892 USA

[5] Univ Penn, Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[6] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA

[7] Vanderbilt Univ, Med Ctr, Dept Med, Div Hematol & Oncol, Nashville, TN 37232 USA

[8] Vanderbilt Univ, Sch Med, Dept Med, Div Allergy Pulm & Crit Care Med, Nashville, TN 37232 USA

[9] H Lee Moffitt Canc Ctr & Res Inst, Dept Blood & Marrow Transplantat & Cellular Immun, Tampa, FL 33612 USA

[10] Vanderbilt Univ, Sch Med, Vanderbilt Inst Infect Immunol & Inflammat, Vanderbilt Ctr Immunobiol, Nashville, TN 37232 USA

来源：

CELL | 2018年 / 175卷 / 07期

基金：

美国国家卫生研究院;

关键词：

T-HELPER-1; CELL; T-CELLS; ACTIVATION; ANTIGEN; GROWTH; INHIBITION; CHROMATIN; PROTEINS; BALANCE; BIOLOGY;

D O I：

10.1016/j.cell.2018.10.001

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：1780 / +

页数：35

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