The energy sensor AMPK orchestrates metabolic and translational adaptation in expanding T helper cells. Issue 4 (14th March 2021)

• Record Type: Journal Article
• Authors: Mayer, Katharina A.; Smole, Ursula; Zhu, Ci; Derdak, Sophia; Minervina, Anastasia A.; Salnikova, Maria; Witzeneder, Nadine; Christamentl, Anna; Boucheron, Nicole; Waidhofer‐Söllner, Petra; Trauner, Michael; Hoermann, Gregor; Schmetterer, Klaus G.; Mamedov, Ilgar Z.; Bilban, Martin; Ellmeier, Wilfried; Pickl, Winfried F.; Gualdoni, Guido A.; Zlabinger, Gerhard J.
• Is Part Of: FASEB journal. Volume 35:Issue 4(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-03-14
• Subjects: AMPK -- cellular metabolism -- T cell -- translation; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.202001763RR
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract: 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.