Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
The Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Cell Rep. 2019 Sep 17;28(12):3011-3021.e4. doi: 10.1016/j.celrep.2019.08.034.
T cell stimulation is metabolically demanding. To exit quiescence, T cells rely on environmental nutrients, including glucose and the amino acids glutamine, leucine, serine, and arginine. The expression of transporters for these nutrients is tightly regulated and required for T cell activation. In contrast to these amino acids, which are essential or require multi-step biosynthesis, alanine can be made from pyruvate by a single transamination. Here, we show that extracellular alanine is nevertheless required for efficient exit from quiescence during naive T cell activation and memory T cell restimulation. Alanine deprivation leads to metabolic and functional impairments. Mechanistically, this vulnerability reflects the low expression of alanine aminotransferase, the enzyme required for interconverting pyruvate and alanine, whereas activated T cells instead induce alanine transporters. Stable isotope tracing reveals that alanine is not catabolized but instead supports protein synthesis. Thus, T cells depend on exogenous alanine for protein synthesis and normal activation.
T 细胞的刺激需要消耗大量代谢物。为了从静息状态中退出，T 细胞依赖于环境中的营养物质，包括葡萄糖以及氨基酸谷氨酰胺、亮氨酸、丝氨酸和精氨酸。这些营养物质的转运蛋白的表达受到严格调控，是 T 细胞激活所必需的。与这些必需氨基酸或需要多步生物合成的氨基酸不同，丙氨酸可以通过单一转氨基作用由丙酮酸生成。在这里，我们表明，在幼稚 T 细胞激活和记忆 T 细胞再刺激过程中，细胞外的丙氨酸对于有效地从静息状态中退出仍然是必需的。丙氨酸剥夺会导致代谢和功能障碍。从机制上讲，这种脆弱性反映了将丙酮酸和丙氨酸相互转化所需的酶——丙氨酸氨基转移酶表达水平较低，而激活的 T 细胞则会诱导丙氨酸转运蛋白的表达。稳定同位素示踪表明，丙氨酸不是被分解代谢，而是支持蛋白质合成。因此，T 细胞依赖于外源性丙氨酸来进行蛋白质合成和正常激活。
