The Translational Machinery of Human CD4+ T Cells Is Poised for Activation and Controls the Switch from Quiescence to Metabolic Remodeling

Ricciardi, Sara; Manfrini, Nicola; Alfieri, Roberta; Calamita, Piera; Crosti, Maria Cristina; Gallo, Simone; Müller, Rolf; Pagani, Massimiliano; Abrignani, Sergio; Biffo, Stefano

doi:10.1016/j.cmet.2018.09.010

Cited by 47 publications

(68 citation statements)

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“…From our dataset, the mRNAs that were most highly translated in naïve T cells were enriched for genes in pathways related to mitochondrion and oxidative phosphorylation, processes linked to mTOR signaling . An independent publication utilized an alternate approach to analyze translation, namely transcriptomic and proteomic analysis of T cells, and found that naive cells accumulate mRNAs for glycolysis and fatty acid synthesis, leading to the hypothesis that these genes contribute to the ability of T cells to rapidly undergo metabolic reprogramming upon TCR stimulation . We also analyzed Rasgrp1 Anaef T cells from young mice, which were just at the cusp of the immunopathology becoming penetrant, in this ribosome profiling study.…”

Section: Tonic Signals From Seeing Selfmentioning

confidence: 99%

mTOR and other effector kinase signals that impact T cell function and activity

Myers

Wheeler

Roose

2019

Immunological Reviews

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T cells play important roles in autoimmune diseases and cancer. Following the cloning of the T cell receptor (TCR), the race was on to map signaling proteins that contributed to T cell activation downstream of the TCR as well as co-stimulatory molecules such as CD28. We term this "canonical TCR signaling" here. More recently, it has been appreciated that T cells need to accommodate increased metabolic needs that stem from T cell activation in order to function properly. A central role herein has emerged for mechanistic/mammalian target of rapamycin (mTOR). In this review we briefly cover canonical TCR signaling to set the stage for discussion on mTOR signaling, mRNA translation, and metabolic adaptation in T cells. We also discuss the role of mTOR in follicular helper T cells, regulatory T cells, and other T cell subsets. Our lab recently uncovered that "tonic signals", which pass through proximal TCR signaling components, are robustly and selectively transduced to mTOR to promote baseline translation of various mRNA targets. We discuss insights on (tonic) mTOR signaling in the context of T cell function in autoimmune diseases such as lupus as well as in cancer immunotherapy through CAR-T cell or checkpoint blockade approaches. K E Y W O R D Sautoimmune, cancer, mammalian target of rapamycin, signaling, T cell, tonic | 135 MYERS Et al

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Section: Tonic Signals From Seeing Selfmentioning

confidence: 99%

mTOR and other effector kinase signals that impact T cell function and activity

Myers

Wheeler

Roose

2019

Immunological Reviews

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“…CD4 + T cells are operating at proportional levels to machinery available to develop an appropriate response to an energetic demand. Taken together, these data may suggest an alteration in mitochondrial metabolic phenotypes of CD4 + T cells, as T helper subsets have been shown to have differing metabolic phenotypes 51,52 . We realize that this study was limited in assessing the contribution of specific T helper subset to overall mitochondrial function.…”

Section: Discussionmentioning

confidence: 79%

“…S3, S4, S2). A recent study of human T cells show translational machinery as a key facilitator in T cell metabolic reprogramming 51 . In corroboration with data from others 59 , our results showed that mRNA expression is a poor indicator of the changes in metabolism occurring at the protein level during T cell activation.…”

Section: Discussionmentioning

confidence: 99%

Lactation stage impacts the glycolytic function of bovine CD4+ T cells during ex vivo activation

Eder

Gorden

Lippolis

et al. 2020

Sci Rep

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Dairy cattle undergo dynamic physiological changes over the course of a full lactation into the dry period, which impacts their immunocompetence. During activation, t cells undergo a characteristic rewiring to increase the uptake of glucose and metabolically reprogram to favor aerobic glycolysis over oxidative phosphorylation. to date it remains to be completely elucidated how the altered energetic demands associated with lactation in dairy cows impacts t cell metabolic reprogramming. thus, in our ex vivo studies we have examined the influence of stage of lactation (early lactation into the dry period) on cellular metabolism in activated bovine CD4 + t cells. Results showed higher rates of glycolytic function in activated CD4 + t cells from late lactation and dry cows compared to cells from early and mid-lactation cows. Similarly, protein and mRNA expression of cytokines were higher in CD4 + t cells from dry cows than CD4 + T cells from lactating cows. The data suggest CD4 + t cells from lactating cows have an altered metabolic responsiveness that could impact the immunocompetence of these animals, particularly those in early lactation, and increase their susceptibility to infection.Physiological stresses of pregnancy and lactation are energetically demanding, with glucose being shuttled to mammary glands and/or fetus depending on lactation stage and gestation 1 . Though ruminants rely heavily on volatile fatty acids, specifically acetate and propionate for energy in whole-body physiology, bovine lymphocytes rely on glucose as their major energy source. During lactation, cells are in competition for glucose with the mammary gland, as it is required for lactose synthesis 2,3 . Like other species, increased glucose uptake is necessary during bovine T cell activation 4,5 .Previous research shows metabolic reprogramming occurring within T cells during activation. Metabolic reprogramming refers to "the Warburg effect", a phenomenon first described in cancer cells, which utilize aerobic glycolysis in oxygen-rich environments 6 . This phenomenon has since been reported in many immune cells, including T cells 7-10 . CD4 + T cells in a resting state utilize oxidative phosphorylation, but with engagement of the T cell receptor (TCR) and CD28, glucose uptake is increased and downstream signaling within the cell occurs 4,11 . This metabolic switch enables cells to utilize mitochondrial respiration, i.e. oxidative phosphorylation (OXPHOS) to upregulate mitochondrial biogenesis during activation to increase the generation of biomolecules necessary for clonal expansion 12,13 while simultaneously increasing the glycolytic rate of the cell. An increase in glycolysis is essential to cell growth and proliferation 4 . Further, aerobic glycolysis regulates immunity by means of glycolytic enzymes; for example, GAPDH, has a role as an RNA-binding protein to regulate post-transcriptional expression of cytokines, like IFN-γ 14 .How T cells from cattle in different lactation stages or in dry cows metabolically reprogram is not yet underst...

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“…In particular, in the context of glucose metabolism an unexpected observation was that Myc was not required for protein expression of the glucose transporters Slc2a1 and Slc2a3 in activated T cells. This was surprising, given previous observations that Myc deletion reduced Slc2a1 and Slc2a3 mRNA (Wang et al, 2011) and highlights the value of a proteomics approach to quantify the expression patterns of proteins where there may be a disconnect between mRNA and protein expression due to translational regulation (Ricciardi et al, 2018). The expression of both glucose and lactate transporters are key for glycolytic flux (Tanner et al, 2018) and the fact that these are differentially controlled by Myc reveals that upregulation of metabolic pathways during T cell activation is more complex than a simple activation switch or amplifier mediated by a single transcription factor (Nie et al, 2012).…”

Section: Discussionmentioning

confidence: 87%

“…T cell immune activation is associated with increases in mRNA translation, amino acid transport and protein synthesis all of which shape the execution of the T cell transcriptional program and completely reshape the T cell proteome (Araki et al, 2017;Geiger et al, 2016;Howden et al, 2019;Ricciardi et al, 2018;Sinclair et al, 2013). Hence, one way to gain a full and unbiased understanding of how Myc controls T cell metabolism and T cell function is an in-depth analysis of how Myc shapes T cell proteomes.…”

Section: Introductionmentioning

confidence: 99%

Quantitative analysis of how Myc controls T cell proteomes and metabolic pathways during T cell activation

Marchingo

Sinclair

Howden

et al. 2019

Preprint

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T cell expansion and differentiation are critically dependent on the transcription factor c-Myc (Myc). Herein we use quantitative mass-spectrometry to reveal how Myc controls antigen receptor driven cell growth and proteome restructuring in T cells. Analysis of copy numbers per cell of >7000 proteins provides new understanding of the selective role of Myc in controlling the protein machinery that govern T cell fate. The data identify both Myc dependent and independent metabolic processes in immune activated T cells. We uncover that a primary function of Myc is to control expression of multiple amino acid transporters and that loss of a single Myc-controlled amino acid transporter effectively phenocopies the impact of Myc deletion. This study provides a comprehensive map of how Myc selectively shapes T cell phenotypes, revealing that Myc induction of amino acid transport is pivotal for subsequent bioenergetic and biosynthetic programs and licences T cell receptor driven proteome reprogramming.

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The Translational Machinery of Human CD4+ T Cells Is Poised for Activation and Controls the Switch from Quiescence to Metabolic Remodeling

Cited by 47 publications

References 0 publications

mTOR and other effector kinase signals that impact T cell function and activity

mTOR and other effector kinase signals that impact T cell function and activity

Lactation stage impacts the glycolytic function of bovine CD4+ T cells during ex vivo activation

Quantitative analysis of how Myc controls T cell proteomes and metabolic pathways during T cell activation

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