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.

• Keywords
• AMPK, T cell, cellular metabolism, translation,
• MeSH
• Adenylate Kinase genetics   metabolism   MeSH
• Lymphocyte Activation MeSH
• Th17 Cells physiology   MeSH
• CD4-Positive T-Lymphocytes MeSH
• DNA-Binding Proteins genetics   metabolism   MeSH
• Adaptation, Physiological MeSH
• Colitis immunology   MeSH
• RNA, Messenger genetics   metabolism   MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Adoptive Transfer MeSH
• Gene Expression Regulation, Enzymologic MeSH
• T-Lymphocytes, Regulatory physiology   MeSH
• T-Lymphocytes, Helper-Inducer physiology   MeSH
• Th1 Cells physiology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adenylate Kinase MeSH
• DNA-Binding Proteins MeSH
• RNA, Messenger MeSH
• Rag2 protein, mouse MeSH Browser