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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Bantug GR, Galluzzi L, Kroemer G, Hess C. The spectrum of T cell metabolism in health and disease. Nat Rev Immunol. 2018;18:19‐34. PubMed

Ron‐Harel N, Santos D, Ghergurovich JM, et al. Mitochondrial biogenesis and proteome remodeling promote one‐carbon metabolism for T cell activation. Cell Metab. 2016;24:104‐117. PubMed PMC

van der Windt GJW, Everts B, Chang C‐H, et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2012;36:68‐78. PubMed PMC

Michalek RD, Gerriets VA, Jacobs SR, et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol. 2011;186:3299‐3303. PubMed PMC

Macintyre AN, Gerriets VA, Nichols AG, et al. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab. 2014;20:61‐72. PubMed PMC

Jacobs SR, Herman CE, Maciver NJ, et al. Glucose uptake is limiting in T cell activation and requires CD28‐mediated Akt‐dependent and independent pathways. J Immunol. 2008;180:4476‐4486. PubMed PMC

Wei J, Raynor J, Nguyen T‐LM, Chi H. Nutrient and metabolic sensing in T cell responses. Front Immunol. 2017;8:247. 10.3389/fimmu.2017.00247 PubMed DOI PMC

Sinclair LV, Rolf J, Emslie E, Shi Y‐B, Taylor PM, Cantrell DA. Control of amino‐acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol. 2013;14:500‐508. PubMed PMC

Johnson MO, Wolf MM, Madden MZ, et al. Distinct regulation of Th17 and Th1 cell differentiation by glutaminase‐dependent metabolism. Cell. 2018;175:1780‐1795.e19. PubMed PMC

Ma EH, Bantug G, Griss T, et al. Serine is an essential metabolite for effector T cell expansion. Cell Metab. 2017;25:345‐357. PubMed

Ron‐Harel N, Ghergurovich JM, Notarangelo G, et al. T cell activation depends on extracellular alanine. Cell Rep. 2019;28:3011‐3021.e4. PubMed PMC

Berod L, Friedrich C, Nandan A, et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med. 2014;20:1327‐1333. PubMed

Raud B, Roy DG, Divakaruni AS, et al. Etomoxir actions on regulatory and memory T cells are independent of Cpt1a‐mediated fatty acid oxidation. Cell Metab. 2018;28:504‐515.e7. PubMed PMC

Gualdoni GA, Mayer KA, Göschl L, Boucheron N, Ellmeier W, Zlabinger GJ. The AMP analog AICAR modulates the Treg/Th17 axis through enhancement of fatty acid oxidation. FASEB J. 2016;30:3800‐3809. PubMed

Carr EL, Kelman A, Wu GS, et al. Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. J Immunol. 2010;185:1037‐1044. PubMed PMC

Yin Y, Choi S‐C, Xu Z, et al. Normalization of CD4+ T cell metabolism reverses lupus. Sci Transl Med. 2015;7:274ra18. PubMed PMC

Lin S‐C, Hardie DG. AMPK: sensing glucose as well as cellular energy status. Cell Metab. 2018;27:299‐313. PubMed

Blagih J, Coulombe F, Vincent EE, et al. The energy sensor AMPK Regulates T cell metabolic adaptation and effector responses in vivo. Immunity. 2015;42:41‐54. PubMed

Hardie DG. Molecular pathways: is AMPK a friend or a foe in cancer? Clin Cancer Res. 2015;21:3836‐3840. PubMed PMC

Chiche J, Reverso‐Meinietti J, Mouchotte A, et al. GAPDH expression predicts the response to R‐CHOP, the tumor metabolic status, and the response of DLBCL patients to metabolic inhibitors. Cell Metab. 2019;29:1243‐1257.e10. PubMed

Guma M, Wang Y, Viollet B, Liu‐Bryan R. AMPK activation by A‐769662 controls IL‐6 expression in inflammatory arthritis. PLoS ONE. 2015;10:e0140452. PubMed PMC

Kang KY, Kim Y‐K, Yi H, et al. Metformin downregulates Th17 cells differentiation and attenuates murine autoimmune arthritis. Int Immunopharmacol. 2013;16:85‐92. PubMed

Nath N, Giri S, Prasad R, Salem ML, Singh AK, Singh I. 5‐aminoimidazole‐4‐carboxamide ribonucleoside: a novel immunomodulator with therapeutic efficacy in experimental autoimmune encephalomyelitis. J Immunol. 2005;175:566‐574. PubMed

Gualdoni GA, Mayer KA, Kapsch A‐M, et al. Rhinovirus induces an anabolic reprogramming in host cell metabolism essential for viral replication. Proc Natl Acad Sci. 2018;115:E7158‐E7165. PubMed PMC

Eri R, McGuckin MA, Wadley R. T cell transfer model of colitis: a great tool to assess the contribution of T cells in chronic intestinal inflammation. In: Ashman, RB , ed. Leucocytes. Totowa, NJ: Humana Press; 2012:261‐275, vol. 844. PubMed

Wirtz S, Neufert C, Weigmann B, Neurath MF. Chemically induced mouse models of intestinal inflammation. Nat Protoc. 2007;2:541‐546. PubMed

Bouladoux N, Harrison OJ, Belkaid Y. The mouse model of infection with Citrobacter rodentium . Curr Protoc Immunol. 2017;119:19.15.1‐19.15.25. PubMed PMC

Smole U, Gour N, Phelan J, et al. Serum amyloid A is a soluble pattern recognition receptor that drives type 2 immunity. Nat Immunol. 2020;21:756‐765. PubMed PMC

Dobin A, Davis CA, Schlesinger F, et al. STAR: ultrafast universal RNA‐seq aligner. Bioinformatics. 2013;29:15‐21. PubMed PMC

Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA‐seq data with DESeq2. Genome Biol. 2014;15:550. PubMed PMC

Shugay M, Britanova OV, Merzlyak EM, et al. Towards error‐free profiling of immune repertoires. Nat Methods. 2014;11:653‐655. PubMed

Bolotin DA, Poslavsky S, Mitrophanov I, et al. MiXCR: software for comprehensive adaptive immunity profiling. Nat Methods. 2015;12:380‐381. PubMed

Shugay M, Bagaev DV, Turchaninova MA, et al. VDJtools: unifying post‐analysis of T Cell receptor repertoires. PLoS Comput Biol. 2015;11:e1004503. PubMed PMC

Inoki K, Zhu T, Guan K‐L. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115:577‐590. PubMed

Gwinn DM, Shackelford DB, Egan DF, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008;30:214‐226. PubMed PMC

Huang J, Manning BD. The TSC1‐TSC2 complex: a molecular switchboard controlling cell growth. Biochem J. 2008;412:179‐190. PubMed PMC

Lee PP, Fitzpatrick DR, Beard C, et al. A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity. 2001;15:763‐774. PubMed

Tamás P, Hawley SA, Clarke RG, et al. Regulation of the energy sensor AMP‐activated protein kinase by antigen receptor and Ca2+ in T lymphocytes. J Exp Med. 2006;203:1665‐1670. PubMed PMC

MacIver NJ, Blagih J, Saucillo DC, et al. The liver kinase B1 Is a central regulator of T cell development, activation, and metabolism. J Immunol. 2011;187:4187‐4198. PubMed PMC

Lanna A, Henson SM, Escors D, Akbar AN. The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells. Nat Immunol. 2014;15:965‐972. PubMed PMC

Lindqvist LM, Tandoc K, Topisirovic I, Furic L. Cross‐talk between protein synthesis, energy metabolism and autophagy in cancer. Curr Opin Genet Dev. 2018;48:104‐111. PubMed PMC

Piccirillo CA, Bjur E, Topisirovic I, Sonenberg N, Larsson O. Translational control of immune responses: from transcripts to translatomes. Nat Immunol. 2014;15:503‐511. PubMed

Araki K, Morita M, Bederman AG, et al. Translation is actively regulated during the differentiation of CD8+ effector T cells. Nat Immunol. 2017;18:1046‐1057. PubMed PMC

Katzman SD, Hoyer KK, Dooms H, et al. Opposing functions of IL‐2 and IL‐7 in the regulation of immune responses. Cytokine. 2011;56:116‐121. PubMed PMC

Kumase F, Takeuchi K, Morizane Y, et al. AMPK‐activated protein kinase suppresses Ccr2 expression by inhibiting the NF‐κB pathway in RAW264.7 macrophages. PLoS ONE. 2016;11:e0147279. PubMed PMC

Yoo HS, Lee K, Na K, et al. Mesenchymal stromal cells inhibit CD25 expression via the mTOR pathway to potentiate T‐cell suppression. Cell Death Dis. 2017;8:e2632. PubMed PMC

Rao E, Zhang Y, Li Q, et al. AMPK‐dependent and independent effects of AICAR and compound C on T‐cell responses. Oncotarget. 2016;7:33783‐33795. PubMed PMC

Ma EH, Verway MJ, Johnson RM, et al. Metabolic profiling using stable isotope tracing reveals distinct patterns of glucose utilization by physiologically activated CD8+ T cells. Immunity. 2019;51:856‐870.e5. PubMed

Wherry EJ, Ha S‐J, Kaech SM, et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity. 2007;27:670‐684. PubMed

Tan H, Yang K, Li Y, et al. Integrative proteomics and phosphoproteomics profiling reveals dynamic signaling networks and bioenergetics pathways underlying T cell activation. Immunity. 2017;46:488‐503. PubMed PMC

Delgoffe GM, Kole TP, Zheng Y, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity. 2009;30:832‐844. PubMed PMC

Yang K, Shrestha S, Zeng H, et al. T cell exit from quiescence and differentiation into Th2 cells depend on Raptor‐mTORC1‐mediated metabolic reprogramming. Immunity. 2013;39:1043‐1056. PubMed PMC

Zeng H, Yang K, Cloer C, Neale G, Vogel P, Chi H. mTORC1 couples immune signals and metabolic programming to establish T(reg)‐cell function. Nature. 2013;499:485‐490. PubMed PMC

Zeng H, Chi H. mTOR signaling in the differentiation and function of regulatory and effector T cells. Curr Opin Immunol. 2017;46:103‐111. PubMed PMC

Yang K, Blanco DB, Neale G, et al. Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signalling. Nature. 2017;548:602‐606. PubMed PMC

Tamás P, Macintyre A, Finlay D, et al. LKB1 is essential for the proliferation of T‐cell progenitors and mature peripheral T cells. Eur J Immunol. 2010;40:242‐253. PubMed PMC

Xie M, Zhang D, Dyck JRB, et al. A pivotal role for endogenous TGF‐beta‐activated kinase‐1 in the LKB1/AMP‐activated protein kinase energy‐sensor pathway. Proc Natl Acad Sci USA. 2006;103:17378‐17383. PubMed PMC

Momcilovic M, Hong S‐P, Carlson M. Mammalian TAK1 activates Snf1 protein kinase in yeast and phosphorylates AMP‐activated protein kinase in vitro. J Biol Chem. 2006;281:25336‐25343. PubMed

Rao E, Zhang Y, Zhu G, et al. Deficiency of AMPK in CD8+ T cells suppresses their anti‐tumor function by inducing protein phosphatase‐mediated cell death. Oncotarget. 2015;6:7944‐7958. PubMed PMC

Mayer A, Denanglaire S, Viollet B, Leo O, Andris F. AMP‐activated protein kinase regulates lymphocyte responses to metabolic stress but is largely dispensable for immune cell development and function. Eur J Immunol. 2008;38:948‐956. PubMed

Vincent EE, Coelho PP, Blagih J, Griss T, Viollet B, Jones RG. Differential effects of AMPK agonists on cell growth and metabolism. Oncogene. 2015;34:3627‐3639. PubMed PMC