安普克
T细胞
细胞生物学
生物
T辅助细胞
免疫系统
蛋白激酶A
免疫学
激酶
作者
Katharina A. Mayer,Ursula Smole,Ci Zhu,Sophia Derdak,Anastasia A. Minervina,Maria A. Salnikova,Nadine Witzeneder,Anna Christamentl,Nicole Boucheron,Petra Waidhofer‐Söllner,Michael Trauner,Gregor Hoermann,Klaus G. Schmetterer,Ilgar Z. Mamedov,Martin Bilban,Wilfried Ellmeier,Winfried F. Pickl,Guido A. Gualdoni,Gerhard J. Zlabinger
标识
DOI:10.1096/fj.202001763rr
摘要
The importance of cellular metabolic adaptation in inducing robust T cell responses is well established. However, the mechanism by which T cells link information regarding nutrient supply to clonal expansion and effector function is still enigmatic. Herein, we report that the metabolic sensor adenosine monophosphate-activated protein kinase (AMPK) is a critical link between cellular energy demand and translational activity and, thus, orchestrates optimal expansion of T cells in vivo. AMPK deficiency did not affect T cell fate decision, activation, or T effector cell generation; however, the magnitude of T cell responses in murine in vivo models of T cell activation was markedly reduced. This impairment was global, as all T helper cell subsets were similarly sensitive to loss of AMPK which resulted in reduced T cell accumulation in peripheral organs and reduced disease severity in pathophysiologically as diverse models as T cell transfer colitis and allergic airway inflammation. T cell receptor repertoire analysis confirmed similar clonotype frequencies in different lymphoid organs, thereby supporting the concept of a quantitative impairment in clonal expansion rather than a skewed qualitative immune response. In line with these findings, in-depth metabolic analysis revealed a decrease in T cell oxidative metabolism, and gene set enrichment analysis indicated a major reduction in ribosomal biogenesis and mRNA translation in AMPK-deficient T cells. We, thus, provide evidence that through its interference with these delicate processes, AMPK orchestrates the quantitative, but not the qualitative, manifestation of primary T cell responses in vivo.
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