在急性移植物抗宿主病 (GVHD) 期间，同种异体 T 细胞会重新编程其代谢，这一过程涉及细胞能量传感器 AMP 激活蛋白激酶 (AMPK)。供体 T 细胞中 AMPK 的缺失可限制 GVHD，但仍保留稳态重建和移植物抗白血病 (GVL) 效应。在目前的研究中，小鼠 AMPK KO T 细胞在移植后的早期时间点降低了氧化代谢，并且在电子传递链抑制后缺乏糖酵解的补偿性增加。使用针对 AMPK 磷酸化靶标的特异性抗体进行免疫沉淀，确定 AMPK 改变了几种糖酵解酶的相互作用，包括醛缩酶、烯醇化酶、丙酮酸激酶 M (PKM) 和 3-磷酸甘油醛脱氢酶 (GAPDH)，并且酶测定表明醛缩酶和 GAPDH 活性受损在 AMPK KO T 细胞中。重要的是，糖酵解的这些变化与 AMPK KO T 细胞在抗原再刺激后产生大量干扰素 γ (IFNγ) 的能力受损以及随后时间点恢复的供体 CD4 T 细胞总数减少相关。 -移植。缺乏 AMPK 的人类 T 细胞也产生了类似的结果，在体外和体内扩增后糖酵解补偿均受损。 GVHD 结果也反映了小鼠模型的结果，CD4/CD8 比率降低，疾病严重程度显着改善。这些数据共同强调了 AMPK 在控制小鼠和人类 T 细胞氧化和糖酵解代谢中的重要作用，并支持进一步研究 AMPK 抑制作为未来 GVHD 治疗的潜在临床目标。版权所有 © 2024 美国血液学会。

Allogeneic T cells reprogram their metabolism during acute graft-versus-host disease (GVHD) in a process involving the cellular energy sensor AMP-activated protein kinase (AMPK). Deletion of AMPK in donor T cells limits GVHD but still preserves homeostatic reconstitution and graft-versus-leukemia (GVL) effects. In the current studies, murine AMPK KO T cells decreased oxidative metabolism at early timepoints post-transplant and lacked a compensatory increase in glycolysis following inhibition of the electron transport chain. Immunoprecipitation using an antibody specific to phosphorylated targets of AMPK determined that AMPK modified interactions of several glycolytic enzymes including aldolase, enolase, pyruvate kinase M (PKM), and glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and enzyme assays indicated impaired aldolase and GAPDH activity in AMPK KO T cells. Importantly, these changes in glycolysis correlated with both an impaired ability of AMPK KO T cells to produce significant amounts of interferon gamma (IFNγ) upon antigenic re-stimulation and a decrease in the total number of donor CD4 T cells recovered at later time points post-transplant. Human T cells lacking AMPK gave similar results, with glycolytic compensation impaired both in vitro and following expansion in vivo. GVHD results also mirrored those of the murine model, with reduced CD4/CD8 ratios and a significant improvement in disease severity. Together these data highlight a significant role for AMPK in controlling oxidative and glycolytic metabolism in both murine and human T cells and endorse further study of AMPK inhibition as a potential clinical target for future GVHD therapies.Copyright © 2024 American Society of Hematology.