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.2018.08.009

Cited by 135 publications

(111 citation statements)

References 57 publications

(77 reference statements)

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“…Moreover, these changes in real-time respiration are supported by earlier work showing remodeling of glycolysis, the TCA cycle and OXPHOS following T cell activation 29,39,40 .…”

Section: Increased Respiration and Downstream Pathway Signaling In Acsupporting

confidence: 73%

“…The association of immune and metabolic states has been extensively studied in T cell biology. Increased utilization of glycolysis, OXPHOS, and fatty acid synthesis following T cell receptor stimulation 1,34,39,[54][55][56] . In this study, we confirmed these findings and further demonstrated the involvement of the PPP, fatty acid oxidation, antioxidant level, and arginine synthesis pathways post activation.…”

Section: Discussionmentioning

confidence: 99%

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A novel strategy for single-cell metabolic analysis highlights dynamic changes in immune subpopulations

Ahl

Hopkins

Xiang

et al. 2020

Preprint

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A complex interaction of anabolic and catabolic metabolism underpins the ability of leukocytes to mount an immune response. Their capacity to respond and adapt to changing environments by metabolic reprogramming is crucial to their effector function. However, current methods lack the ability to interrogate this network of metabolic pathways at the single cell level within a heterogeneous population. Here we present Met-Flow, a novel flow cytometry-based method that captures the metabolic state of immune cells by targeting key proteins and rate-limiting enzymes across multiple pathways. We demonstrate the ability to simultaneously measure divergent metabolic profiles and dynamic remodeling in human peripheral blood mononuclear cells. Using Met-Flow, we discovered that glucose restriction and metabolic remodeling drive the expansion of an inflammatory central memory T cell subset. This method captures the complex metabolic state of any cell as it relates to its phenotype and function, leading to a greater understanding of the role of metabolic heterogeneity in immune responses.

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“…Moreover, these changes in real-time respiration are supported by earlier work showing remodeling of glycolysis, the TCA cycle and OXPHOS following T cell activation 29,39,40 .…”

Section: Increased Respiration and Downstream Pathway Signaling In Acsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

A novel strategy for single-cell metabolic analysis highlights dynamic changes in immune subpopulations

Ahl

Hopkins

Xiang

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Recent studies have demonstrated that regulation of mRNA translation by mTORC1 is associated with T-cell activation and effector-cell differentiation. 97,98 Studies have shown that the translatome differs among subsets of effector CD8 + or CD4 + T cells. 97,99 Also, T-cell proteome remodeling appears to be largely regulated at the post-transcriptional level in both CD4 + and CD8 + T cells, [100][101][102] implicating protein translation as a major regulator of T-cell activation and differentiation.…”

Section: Translation Of Proteins Via S6k and 4e-bp Pathwaysmentioning

confidence: 99%

mTOR signaling at the crossroads of environmental signals and T‐cell fate decisions

Huang

Long

Zhou

et al. 2020

Immunological Reviews

136

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The evolutionarily conserved serine/threonine kinase mTOR (mechanistic target of rapamycin) forms the distinct protein complexes mTORC1 and mTORC2 and integrates signals from the environment to coordinate downstream signaling events and various cellular processes. T cells rely on mTOR activity for their development and to establish their homeostasis and functional fitness. Here, we review recent progress in our understanding of the upstream signaling and downstream targets of mTOR. We also provide an updated overview of the roles of mTOR in T‐cell development, homeostasis, activation, and effector‐cell fate decisions, as well as its important impacts on the suppressive activity of regulatory T cells. Moreover, we summarize the emerging roles of mTOR in T‐cell exhaustion and transdifferentiation. A better understanding of the contribution of mTOR to T‐cell fate decisions will ultimately aid in the therapeutic targeting of mTOR in human disease.

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“… AbstractActivation of T cells requires a global surge in cellular protein synthesis, which is accompanied by a large increase in translation initiation 1–4 . A central component of the translation initiation machinery–the multi-subunit eukaryotic initiation factor 3 (eIF3)–is rapidly turned on when quiescent T cells are stimulated 3 .…”

mentioning

confidence: 99%

“…In the immune system, T cell activation involves a burst in translation 1–4 and correlates with assembly of subunit EIF3J with the main eIF3 complex 3 . However, whether eIF3 serves a general or more specific role in T cell activation is not known.…”

mentioning

confidence: 99%

A burst in T cell receptor translation mediated by eIF3 interactions with T cell receptor mRNAs

Silva

Ferguson

Smith

et al. 2019

Preprint

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39Activation of T cells requires a global surge in cellular protein synthesis, which is 40 accompanied by a large increase in translation initiation [1][2][3][4] . A central component of the 41 translation initiation machinery-the multi-subunit eukaryotic initiation factor 3 (eIF3)-is 42 rapidly turned on when quiescent T cells are stimulated 3 . However, the precise role eIF3 43 plays in activated T cells is not known. Using a global transcriptome cross-linking 44 approach, we show that human eIF3 interacts with a distinct set of mRNAs in activated 45 Jurkat cells. A subset of these mRNAs, including those encoding the T cell receptor (TCR) 46 subunits TCRA and TCRB, crosslink to eIF3 across the entire length of the mRNA. 47Main 55 Several lines of evidence indicate eIF3 serves specialized roles in cellular translation, by 56 recognizing specific RNA structures in the 5'-untranslated regions (5'-UTRs) of target 57 mRNAs 5 , binding the 7-methyl-guanosine (m 7 G) cap 6 or through interactions with N-6-58 methyl-adenosine (m 6 A) post-transcriptional modifications in mRNAs 7 . Binding to these 59 cis-regulatory elements in mRNA can lead to translation activation or repression, 60 depending on the RNA sequence and structural context 5,7,8 . These functions for eIF3 can 61 aid cell proliferation 5 , or allow cells to rapidly adapt to stress such as heat shock 7 . 62 Additionally, eIF3 plays an important role in the development of specific tissues 9-11 . 63 64 In the immune system, T cell activation involves a burst in translation 1-4 and correlates 65 with assembly of subunit EIF3J with the main eIF3 complex 3 . However, whether eIF3 66 serves a general or more specific role in T cell activation is not known. To delineate how 67 eIF3 contributes to T cell activation, we first identified mRNAs that directly interact with 68 eIF3 in Jurkat cells activated for 5 hours with ionomycin and phorbol 12-myristate 13-69 acetate (I+PMA), or in non-activated Jurkat cells as a control, using photoactivatable 70 ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) 5,12,13 (Fig. 71 1a). We used Jurkat cells as a model for T cells, as PAR-CLIP experiments require a 72 large number of cells labeled with 4-thiouridine at a non-toxic concentration 14 . Jurkat cells 73 also have a defined T cell receptor and transcriptome, avoiding the donor-to-donor 74 variability of primary T cells. In the Jurkat PAR-CLIP experiments, RNA crosslinked to 75 eight of the thirteen eIF3 subunits, as identified by mass spectrometry: subunits EIF3A, 76 EIF3B, EIF3D and EIF3G as seen in HEK293T cells 5 , as well as subunits EIF3C, EIF3E, 77 De Silva et al. 4EIF3F, and EIF3L (Fig. 1b, Extended Data Fig. 1, Supplementary Table 1). In activated 78 Jurkat cells, eIF3 crosslinked to a substantially larger number of mRNAs compared to the 79 non-activated cells (Extended Data Figs. 2 and 3, Supplementary Tables 2 and 3). 80 Notably, eIF3 interacted with a completely new suite of mRNAs in activated Jurkat cells, 81 co...

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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 135 publications

References 57 publications

A novel strategy for single-cell metabolic analysis highlights dynamic changes in immune subpopulations

A novel strategy for single-cell metabolic analysis highlights dynamic changes in immune subpopulations

mTOR signaling at the crossroads of environmental signals and T‐cell fate decisions

A burst in T cell receptor translation mediated by eIF3 interactions with T cell receptor mRNAs

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