谷氨酰胺
谷氨酰胺酶
细胞毒性T细胞
CD8型
谷氨酰胺分解
生物
T细胞
细胞生物学
癌细胞
化学
生物化学
癌症研究
免疫系统
免疫学
癌症
氨基酸
体外
遗传学
作者
Matthew Z. Madden,Xiang Ye,Channing Chi,Emilie L. Fisher,Melissa M. Wolf,Gabriel A Needle,Jackie E. Bader,Andrew R. Patterson,Bradley I. Reinfeld,Madelyn D. Landis,Emma S Hathaway,Jason E Muka,Richard T. O’Neil,John Karijolich,Mary Philip,Jeffrey C. Rathmell
出处
期刊:Journal of Immunology
[The American Association of Immunologists]
日期:2023-06-21
卷期号:211 (4): 563-575
被引量:4
标识
DOI:10.4049/jimmunol.2200715
摘要
Activated T cells undergo metabolic reprogramming to meet anabolic, differentiation, and functional demands. Glutamine supports many processes in activated T cells, and inhibition of glutamine metabolism alters T cell function in autoimmune disease and cancer. Multiple glutamine-targeting molecules are under investigation, yet the precise mechanisms of glutamine-dependent CD8 T cell differentiation remain unclear. We show that distinct strategies of glutamine inhibition by glutaminase-specific inhibition with small molecule CB-839, pan-glutamine inhibition with 6-diazo-5-oxo-l-norleucine (DON), or by glutamine-depleted conditions (No Q) produce distinct metabolic differentiation trajectories in murine CD8 T cells. T cell activation with CB-839 treatment had a milder effect than did DON or No Q treatment. A key difference was that CB-839-treated cells compensated with increased glycolytic metabolism, whereas DON and No Q-treated cells increased oxidative metabolism. However, all glutamine treatment strategies elevated CD8 T cell dependence on glucose metabolism, and No Q treatment caused adaptation toward reduced glutamine dependence. DON treatment reduced histone modifications and numbers of persisting cells in adoptive transfer studies, but those T cells that remained could expand normally upon secondary Ag encounter. In contrast, No Q-treated cells persisted well yet demonstrated decreased secondary expansion. Consistent with reduced persistence, CD8 T cells activated in the presence of DON had reduced ability to control tumor growth and reduced tumor infiltration in adoptive cell therapy. Overall, each approach to inhibit glutamine metabolism confers distinct effects on CD8 T cells and highlights that targeting the same pathway in different ways can elicit opposing metabolic and functional outcomes.
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