生物
间充质干细胞
细胞生物学
PI3K/AKT/mTOR通路
T细胞
糖酵解
厌氧糖酵解
免疫系统
吲哚胺2,3-双加氧酶
雷帕霉素的作用靶点
干细胞
细胞
间质细胞
免疫学
癌症研究
信号转导
生物化学
新陈代谢
色氨酸
氨基酸
作者
Martin Böttcher,Andreas D. Hofmann,Heiko Bruns,Martina Haibach,Romy Loschinski,Domenica Saul,Andréas Mackensen,Katarina Le Blanc,Regina Jitschin,Dimitrios Mougiakakos
出处
期刊:Stem Cells
[Oxford University Press]
日期:2015-10-20
卷期号:34 (2): 516-521
被引量:50
摘要
Abstract Mesenchymal stromal cells (MSCs) possess numerous regenerative and immune modulating functions. Transplantation across histocompatibility barriers is feasible due to their hypo-immunogenicity. MSCs have emerged as promising tools for treating graft-versus-host disease following allogeneic stem cell transplantation. It is well established that their clinical efficacy is substantially attributed to fine-tuning of T-cell responses. At the same time, increasing evidence suggests that metabolic processes control T-cell function and fate. Here, we investigated the MSCs' impact on the metabolic framework of activated T-cells. In fact, MSCs led to mitigated mTOR signaling. This phenomenon was accompanied by a weaker glycolytic response (including glucose uptake, glycolytic rate, and upregulation of glycolytic machinery) toward T-cell activating stimuli. Notably, MSCs express indoleamine-2,3-dioxygenase (IDO), which mediates T-cell suppressive tryptophan catabolism. Our observations suggest that IDO-induced tryptophan depletion interferes with a tryptophan-sufficiency signal that promotes cellular mTOR activation. Despite an immediate suppression of T-cell responses, MSCs foster a metabolically quiescent T-cell phenotype characterized by reduced mTOR signaling and glycolysis, increased autophagy, and lower oxidative stress levels. In fact, those features have previously been shown to promote generation of long-lived memory cells and it remains to be elucidated how MSC-induced metabolic effects shape in vivo T-cell immunity.
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