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• W2902669448 abstract "Signaling and transcriptional regulation of metabolic reprogramming upon T cell activation has been studied intensively. In this issue of Cell Metabolism, Ricciardi et al., 2018Ricciardi S. Manfrini N. Alfieri R. Calamita P. Crosti M.C. Gallo S. Müller R. Pagani M. Abrignani S. Biffo S. The translational machinery of human CD4+ T cells is poised for activation and controls the switch from quiescence to metabolic remodeling.Cell Metab. 2018; 28 (this issue): 895-906Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar show that translational regulation of key metabolic enzymes GLUT1 and ACC1 plays a novel role in human naive CD4 T cell activation and subset differentiation. Signaling and transcriptional regulation of metabolic reprogramming upon T cell activation has been studied intensively. In this issue of Cell Metabolism, Ricciardi et al., 2018Ricciardi S. Manfrini N. Alfieri R. Calamita P. Crosti M.C. Gallo S. Müller R. Pagani M. Abrignani S. Biffo S. The translational machinery of human CD4+ T cells is poised for activation and controls the switch from quiescence to metabolic remodeling.Cell Metab. 2018; 28 (this issue): 895-906Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar show that translational regulation of key metabolic enzymes GLUT1 and ACC1 plays a novel role in human naive CD4 T cell activation and subset differentiation. CD4+ and CD8+ T cells constitute critical components of the adaptive immune system. Upon antigen recognition, naive T cells undergo prodigious proliferation and differentiate into effector subsets. These functions require robust and distinct bioenergetics and biosynthetic demands. Like most non-proliferating cells, naive T cells are generally considered metabolically quiescent and rely on fatty acid oxidation to maintain homeostasis. However, upon TCR engagement and co-stimulatory signals, naive T cells almost immediately switch from fatty acid oxidation to aerobic glycolysis. After an initial activation or priming process, they enter a rapid proliferating stage accompanied by increased glutaminolysis and fatty acid synthesis. Upon starting to proliferate, they are able to divide every 4 to 6 hr (Rathmell, 2011Rathmell J.C. T cell Myc-tabolism.Immunity. 2011; 35: 845-846Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). Efforts have been made to interrogate how naive T cells are able to achieve this rapid metabolic reprogramming. TCR ligation leads to coordinated upregulation of glucose and amino acid transporters, facilitating nutrient uptake and T cell blastogenesis. Following TCR activation, transcription factors such as Myc, Hif1a, IRF4, SREBP, and ERRα induce and sustain various metabolic genes’ expression necessary to support glycolysis, glutaminolysis, polyamine synthesis, sterol and lipid synthesis, and mitochondria metabolism (MacIver et al., 2013MacIver N.J. Michalek R.D. Rathmell J.C. Metabolic regulation of T lymphocytes.Annu. Rev. Immunol. 2013; 31: 259-283Crossref PubMed Scopus (814) Google Scholar, Pearce et al., 2013Pearce E.L. Poffenberger M.C. Chang C.H. Jones R.G. Fueling immunity: insights into metabolism and lymphocyte function.Science. 2013; 342: 1242454Crossref PubMed Scopus (822) Google Scholar). Integrating environmental cues, including TCR signaling, growth factors, and nutrient availability, the mechanistic target of rapamycin (mTOR) plays an important role in regulating T cell metabolism and differentiation (Powell and Delgoffe, 2010Powell J.D. Delgoffe G.M. The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism.Immunity. 2010; 33: 301-311Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar). To this end, a major role of mTOR is to regulate the process of protein translation. Ricciardi et al., 2018Ricciardi S. Manfrini N. Alfieri R. Calamita P. Crosti M.C. Gallo S. Müller R. Pagani M. Abrignani S. Biffo S. The translational machinery of human CD4+ T cells is poised for activation and controls the switch from quiescence to metabolic remodeling.Cell Metab. 2018; 28 (this issue): 895-906Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar hypothesized that a translational regulation of T cell metabolism may exist in naive T cells. Sure enough, by analyzing transcriptomic and proteomic datasets of metabolic genes in human naive CD4+ T cells, they discovered genes with abundant mRNA presence that were essentially undetectable at the protein level. Among these genes were the critical metabolic components glucose transporter GLUT1 and acetyl-CoA carboxylase ACC1. Surprisingly, by probing the transcriptomic and proteomic datasets further, Ricciardi et al., 2018Ricciardi S. Manfrini N. Alfieri R. Calamita P. Crosti M.C. Gallo S. Müller R. Pagani M. Abrignani S. Biffo S. The translational machinery of human CD4+ T cells is poised for activation and controls the switch from quiescence to metabolic remodeling.Cell Metab. 2018; 28 (this issue): 895-906Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar found abundant ribosomal and translational machinery in human naive CD4+ T cells. However, compared to TCR-activated cells, polysomal profiles of naive CD4+ T cells showed a high 80S peak, indicating an absence of translation initiation. 4E-BPs bind eIF4E and inhibit the formation of translation initiation complex. At the protein level, Ricciardi et al., 2018Ricciardi S. Manfrini N. Alfieri R. Calamita P. Crosti M.C. Gallo S. Müller R. Pagani M. Abrignani S. Biffo S. The translational machinery of human CD4+ T cells is poised for activation and controls the switch from quiescence to metabolic remodeling.Cell Metab. 2018; 28 (this issue): 895-906Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar found that 4E-BPs outnumbered eIF4E by 2-fold, indicating an inhibited translation state. Using pharmacological inhibitors, Ricciardi et al., 2018Ricciardi S. Manfrini N. Alfieri R. Calamita P. Crosti M.C. Gallo S. Müller R. Pagani M. Abrignani S. Biffo S. The translational machinery of human CD4+ T cells is poised for activation and controls the switch from quiescence to metabolic remodeling.Cell Metab. 2018; 28 (this issue): 895-906Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar were able to show that in human naive CD4+ T cells, upon activation, GLUT1 and ACC1 were regulated at the translational level instead of transcriptional level. These observations suggested an elegant model to explain how naive CD4+ T cells could rapidly switch from fatty acid oxidation to glycolysis and fatty acid synthesis. That is, the “quiescent” naive T cells already had transcribed the genes necessary for such a switch and upon activation merely needed to translate these genes. By employing 4EGi-1, an inhibitor of eIF4E-eIF4G interaction and a biochemical luciferase assay, Ricciardi et al., 2018Ricciardi S. Manfrini N. Alfieri R. Calamita P. Crosti M.C. Gallo S. Müller R. Pagani M. Abrignani S. Biffo S. The translational machinery of human CD4+ T cells is poised for activation and controls the switch from quiescence to metabolic remodeling.Cell Metab. 2018; 28 (this issue): 895-906Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar further went on to show that ACC1 was translationally regulated via its 5′UTR. Importantly, both 4EGi-1, a broad translational inhibitor, and SorA, an ACC1-specific inhibitor, reduced pyruvate, lactate, and OCR of activated T cells, indicating that translational regulation of ACC1 is essential for metabolic reprogramming and crosstalk between glycolysis and mitochondria respiration. As the rate-limiting step in fatty acid synthesis, ACC1 catalyzes the carboxylation of acetyl-CoA to malonyl-CoA. Both glycolysis and the TCA cycle contribute to cytoplasmic acetyl-CoA pool, and this probably explains how ACC1 blockade slows down glycolysis and the TCA cycle. In addition, malonyl-CoA was shown to allosterically bind and inhibit Cpt1a, which is critical for fatty acid flux in mitochondria (Saggerson, 2008Saggerson D. Malonyl-CoA, a key signaling molecule in mammalian cells.Annu. Rev. Nutr. 2008; 28: 253-272Crossref PubMed Scopus (198) Google Scholar). mTOR functions through two different complexes, mTORC1 and mTORC2. mTOR deficiency or inhibition blocks differentiation into Th1, Th2, or Th17 cells under their respective polarizing conditions and leads to T regulatory cells (Tregs) generation (Delgoffe et al., 2009Delgoffe G.M. Kole T.P. Zheng Y. Zarek P.E. Matthews K.L. Xiao B. Worley P.F. Kozma S.C. Powell J.D. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment.Immunity. 2009; 30: 832-844Abstract Full Text Full Text PDF PubMed Scopus (908) Google Scholar). The observation that equivalent ACC1 mRNA levels were detected across all helper CD4+ T cell subsets while protein levels varied prompted Ricciardi et al., 2018Ricciardi S. Manfrini N. Alfieri R. Calamita P. Crosti M.C. Gallo S. Müller R. Pagani M. Abrignani S. Biffo S. The translational machinery of human CD4+ T cells is poised for activation and controls the switch from quiescence to metabolic remodeling.Cell Metab. 2018; 28 (this issue): 895-906Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar to examine the idea that translation might also play a role in regulating CD4+ T cell fate decision. In testing this hypothesis, they found that under Th17 skewing conditions, 4EGi-1 inhibited the generation of IL17-producing cells while increasing Foxp3+ T regulatory cells. Mechanistically, 4EGi-1 treatment decreased RORγt and increased Foxp3, both at the mRNA and protein level. Overall, these findings certainly call into question the idea that naive T cells are quiescent. Indeed, while metabolically they are efficiently fueling themselves via a low level of OXPHOS and fatty acid oxidation, in fact their translational machinery is poised to rapidly fire up the key enzymes essential for robust metabolic reprogramming (Figure 1). To this end, these data shed a novel and exciting new light on T cell metabolic reprogramming. While Ricciardi et al., 2018Ricciardi S. Manfrini N. Alfieri R. Calamita P. Crosti M.C. Gallo S. Müller R. Pagani M. Abrignani S. Biffo S. The translational machinery of human CD4+ T cells is poised for activation and controls the switch from quiescence to metabolic remodeling.Cell Metab. 2018; 28 (this issue): 895-906Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar clearly show that ACC1 is one of the key enzymes that is translationally regulated, several questions remain to be addressed. First, how is the translational machinery poised at the molecular level? Second, TCR signaling induces AMPK activation that in turn phosphorylates and inhibits ACC1 (MacIver et al., 2011MacIver N.J. Blagih J. Saucillo D.C. Tonelli L. Griss T. Rathmell J.C. Jones R.G. The liver kinase B1 is a central regulator of T cell development, activation, and metabolism.J. Immunol. 2011; 187: 4187-4198Crossref PubMed Scopus (169) Google Scholar, Tamás et al., 2006Tamás P. Hawley S.A. Clarke R.G. Mustard K.J. Green K. Hardie D.G. Cantrell D.A. Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes.J. Exp. Med. 2006; 203: 1665-1670Crossref PubMed Scopus (259) Google Scholar). Ricciardi et al., 2018Ricciardi S. Manfrini N. Alfieri R. Calamita P. Crosti M.C. Gallo S. Müller R. Pagani M. Abrignani S. Biffo S. The translational machinery of human CD4+ T cells is poised for activation and controls the switch from quiescence to metabolic remodeling.Cell Metab. 2018; 28 (this issue): 895-906Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar concluded that in human CD4+ T cells, repression of ACC1 bypassed AMPK-driven control based on the observation that the ATP/AMP ratio didn’t change and phosphorylated AMPK was not detected 24 hr after activation. It would be interesting to know if, indeed, AMPK does provide another layer of regulation at earlier time points when AMPK is robustly activated. Third, Ricciardi et al., 2018Ricciardi S. Manfrini N. Alfieri R. Calamita P. Crosti M.C. Gallo S. Müller R. Pagani M. Abrignani S. Biffo S. The translational machinery of human CD4+ T cells is poised for activation and controls the switch from quiescence to metabolic remodeling.Cell Metab. 2018; 28 (this issue): 895-906Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar identified GLUT1 as another translationally poised protein in addition to ACC1. Previous studies have shown that CD28 signaling is a key regulator of GLUT1 expression (Frauwirth et al., 2002Frauwirth K.A. Riley J.L. Harris M.H. Parry R.V. Rathmell J.C. Plas D.R. Elstrom R.L. June C.H. Thompson C.B. The CD28 signaling pathway regulates glucose metabolism.Immunity. 2002; 16: 769-777Abstract Full Text Full Text PDF PubMed Scopus (1003) Google Scholar, Jacobs et al., 2008Jacobs S.R. Herman C.E. Maciver N.J. Wofford J.A. Wieman H.L. Hammen J.J. Rathmell J.C. Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways.J. Immunol. 2008; 180: 4476-4486Crossref PubMed Scopus (548) Google Scholar). In this regard, it would be interesting to know the interplay between these two mechanisms of regulating GLUT1 expression upon T cell activation. Overall, this work provides novel insight regarding metabolic regulation. It will be intriguing to see if translational regulation plays a role in naive CD8+ T cells, resting memory CD8+ T cells, or other cell types that are highly regulated by metabolism, like macrophages. Likewise, it will be of interest to determine whether this model of poised translational repression also plays a role in other genes and genetic programs that are critical for the rapid activation of cells. J.D.P. has equity in Dracen. Also in Sityrx, and Corvus (less than 5%). J.D.P. has consulted for Dracen, Sityrx, Corvus, Aeonian, Sigma, and Quadriga. J.D.P. has received sponsored research money from Abbvie, Quadriga, Dracen, BMS, and Bluebird. J.D.P. has patents licensed by Dracen. The Translational Machinery of Human CD4+ T Cells Is Poised for Activation and Controls the Switch from Quiescence to Metabolic RemodelingRicciardi et al.Cell MetabolismSeptember 6, 2018In BriefRicciardi et al. show that the translation of pre-accumulated mRNAs encoding key players in glycolytic and fatty acid synthesis drives metabolic reprogramming of naive T cells. Upon TCR activation, the poised translational machinery is activated, thereby coordinating the translation of GLUT1 and ACC1 mRNAs and linking metabolism to effector cell fate. Full-Text PDF Open Archive" @default.
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• W2902669448 title "Peeking under the Hood of Naive T Cells" @default.
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