Institute of Life Science, Swansea University Medical School, Swansea, SA2 8PP, UK.
MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Bristol, BS8 2BN, UK.
Nat Commun. 2019 May 3;10(1):2042. doi: 10.1038/s41467-019-10023-4.
Metabolic pathways that regulate T-cell function show promise as therapeutic targets in diverse diseases. Here, we show that at rest cultured human effector memory and central memory CD4+ T-cells have elevated levels of glycolysis and oxidative phosphorylation (OXPHOS), in comparison to naïve T-cells. Despite having low resting metabolic rates, naive T-cells respond to TCR stimulation with robust and rapid increases in glycolysis and OXPHOS. This early metabolic switch requires Akt activity to support increased rates of glycolysis and STAT5 activity for amino acid biosynthesis and TCA cycle anaplerosis. Importantly, both STAT5 inhibition and disruption of TCA cycle anaplerosis are associated with reduced IL-2 production, demonstrating the functional importance of this early metabolic program. Our results define STAT5 as a key node in modulating the early metabolic program following activation in naive CD4+ T-cells and in turn provide greater understanding of how cellular metabolism shapes T-cell responses.
代谢途径调节 T 细胞功能，有望成为多种疾病的治疗靶点。在这里，我们发现与初始 T 细胞相比，静止培养的人类效应记忆和中央记忆 CD4+T 细胞的糖酵解和氧化磷酸化（OXPHOS）水平升高。尽管初始 T 细胞的静息代谢率较低，但它们对 TCR 刺激的反应是糖酵解和 OXPHOS 迅速而显著地增加。这种早期的代谢转换需要 Akt 活性来支持糖酵解速率的增加，需要 STAT5 活性来支持氨基酸合成和 TCA 循环回补。重要的是，STAT5 抑制和 TCA 循环回补的破坏都与 IL-2 产生减少有关，这表明了这一早期代谢程序的重要功能。我们的研究结果将 STAT5 定义为调节初始 CD4+T 细胞激活后早期代谢程序的关键节点，从而更深入地了解细胞代谢如何塑造 T 细胞反应。
