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.

Central European Institute of Technology Masaryk University Brno Czech Republic

Core Facilities Medical University of Vienna Vienna Austria

Department of Genomics of Adaptive Immunity Shemyakin Ovchinnikov Institute of Bioorganic Chemistry Moscow Russia

Department of Laboratory Medicine Medical University of Vienna Vienna Austria

Division of Hematology and Hemostaseology Department of Internal Medicine 1 Medical University of Vienna Vienna Austria

Division of Nephrology and Dialysis Department of Internal Medicine 3 Medical University of Vienna Vienna Austria

Hans Popper Laboratory of Molecular Hepatology Division of Gastroenterology and Hepatology Department of Internal Medicine 3 Medical University of Vienna Vienna Austria

Institute of Immunology Center of Pathophysiology Infectiology and Immunology Medical University of Vienna Vienna Austria

MLL Munich Leukemia Laboratory Munich Germany

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