Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland.
Cell Metab. 2017 Feb 7;25(2):345-357. doi: 10.1016/j.cmet.2016.12.011. Epub 2017 Jan 19.
During immune challenge, T lymphocytes engage pathways of anabolic metabolism to support clonal expansion and the development of effector functions. Here we report a critical role for the non-essential amino acid serine in effector T cell responses. Upon activation, T cells upregulate enzymes of the serine, glycine, one-carbon (SGOC) metabolic network, and rapidly increase processing of serine into one-carbon metabolism. We show that extracellular serine is required for optimal T cell expansion even in glucose concentrations sufficient to support T cell activation, bioenergetics, and effector function. Restricting dietary serine impairs pathogen-driven expansion of T cells in vivo, without affecting overall immune cell homeostasis. Mechanistically, serine supplies glycine and one-carbon units for de novo nucleotide biosynthesis in proliferating T cells, and one-carbon units from formate can rescue T cells from serine deprivation. Our data implicate serine as a key immunometabolite that directly modulates adaptive immunity by controlling T cell proliferative capacity.
在免疫挑战中，T 淋巴细胞会利用合成代谢途径来支持克隆扩增和效应功能的发展。在这里，我们报告了非必需氨基酸丝氨酸在效应 T 细胞反应中的关键作用。T 细胞激活后，上调丝氨酸、甘氨酸、一碳（SGOC）代谢网络的酶，并迅速将丝氨酸加工成一碳代谢。我们表明，即使在葡萄糖浓度足以支持 T 细胞激活、生物能量和效应功能的情况下，细胞外丝氨酸对于 T 细胞的最佳扩增也是必需的。限制饮食中的丝氨酸会损害病原体驱动的 T 细胞在体内的扩增，而不会影响整体免疫细胞稳态。从机制上讲，丝氨酸为增殖 T 细胞中的从头核苷酸合成提供甘氨酸和一碳单位，而来自甲酸盐的一碳单位可以挽救因缺乏丝氨酸而受到的 T 细胞。我们的数据表明，丝氨酸是一种关键的免疫代谢物，通过控制 T 细胞的增殖能力直接调节适应性免疫。
