Division of Cell Signalling and Immunology, University of Dundee, Dundee, UK.
Nat Immunol. 2013 May;14(5):500-8. doi: 10.1038/ni.2556. Epub 2013 Mar 24.
T lymphocytes must regulate nutrient uptake to meet the metabolic demands of an immune response. Here we show that the intracellular supply of large neutral amino acids (LNAAs) in T cells was regulated by pathogens and the T cell antigen receptor (TCR). T cells responded to antigen by upregulating expression of many amino-acid transporters, but a single System L ('leucine-preferring system') transporter, Slc7a5, mediated uptake of LNAAs in activated T cells. Slc7a5-null T cells were unable to metabolically reprogram in response to antigen and did not undergo clonal expansion or effector differentiation. The metabolic catastrophe caused by loss of Slc7a5 reflected the requirement for sustained uptake of the LNAA leucine for activation of the serine-threonine kinase complex mTORC1 and for expression of the transcription factor c-Myc. Control of expression of the System L transporter by pathogens is thus a critical metabolic checkpoint for T cells.
T 淋巴细胞必须调节营养物质摄取以满足免疫应答的代谢需求。在这里,我们表明,T 细胞内的大中性氨基酸(LNAAs)供应受到病原体和 T 细胞抗原受体(TCR)的调节。T 细胞通过上调多种氨基酸转运蛋白的表达来响应抗原,但单一的 System L(“亮氨酸优先系统”)转运蛋白 Slc7a5 介导激活的 T 细胞中 LNAAs 的摄取。Slc7a5 缺陷型 T 细胞无法响应抗原进行代谢重编程,也无法进行克隆扩增或效应器分化。Slc7a5 缺失引起的代谢灾难反映了持续摄取 LNAA 亮氨酸以激活丝氨酸-苏氨酸激酶复合物 mTORC1 和表达转录因子 c-Myc 的需求。因此,病原体对 System L 转运蛋白表达的控制是 T 细胞的一个关键代谢检查点。
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