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

Huang, Hongling; Long, Ling; Zhou, Peipei; Chapman, Nicole M.; Chi, Hongbo

doi:10.1111/imr.12845

Cited by 121 publications

(76 citation statements)

References 266 publications

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“…mTOR acts as part of two protein complexes, with the predominant immunometabolic regulation occurring through the actions of mTOR complex I (mTORC1) that is activated downstream of receptor stimulation of phosphatidylinositol 3‐kinase (PI3K) and Akt. As described by Huang et al 34 the PI3K/Akt/mTORC1 pathway serves as a central mechanism to sense and integrate nutrient availability and signaling to promote T cell metabolism and function. mTORC1 is activated at lysosomes through the combined actions of T cell activation and signaling through PI3K and Akt that lead to activation of the Rheb GTPase and the coordinated sensing of essential amino acids through the sestrin/GATOR complex.…”

Section: Basic Mechanisms That Regulate Immune Metabolismmentioning

confidence: 99%

Immunometabolism: From basic mechanisms to translation

Makowski

Chaib

Rathmell

2020

Immunological Reviews

218

141

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Immunometabolism has emerged as a major mechanism central to adaptive and innate immune regulation. From early observations that inflammatory cytokines were induced in obese adipose tissue and that these cytokines contributed to metabolic disease, it was clear that metabolism and the immunological state are inextricably linked. With a second research wave arising from studies in cancer metabolism to also study the intrinsic metabolic pathways of immune cells themselves and how those pathways influence cell fate and function, immunometabolism is a rapidly maturing area of research. Several key themes and goals drive the field. There is abundant evidence that metabolic pathways are closely tied to cell signaling and differentiation which leads different subsets of immune cells to adopt unique metabolic programs specific to their state and environment. In this way, metabolic signaling drives cell fate. It is also apparent that microenvironment greatly influences cell metabolism.Immune cells adopt programs specific for the tissues where they infiltrate and reside.Ultimately, a central goal of the field is to apply immunometabolism findings to the discovery of novel therapeutic strategies in a wide range of diseases, including cancer, autoimmunity, and metabolic syndrome. This review summarizes these facets of immunometabolism and highlights opportunities for clinical translation. K E Y W O R D S autoimmunity, immune-mediated diseases, infectious diseases, metThis article introduces a series of reviews covering Immunometabolism: From Basic Mechanisms to Translation appearing in Volume 295 of Immunological Reviews.

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Section: Basic Mechanisms That Regulate Immune Metabolismmentioning

confidence: 99%

Immunometabolism: From basic mechanisms to translation

Makowski

Chaib

Rathmell

2020

Immunological Reviews

218

141

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“…the outcome of T-cell activation and proliferation, including functional differentiation and acquisition of memory properties (Huang et al, 2020). Certain amino-acid catabolizing enzymes interfere at various points of this signaling cascade (Figure 3).…”

Section: The Effect Of Amino-acid Catabolizing Enzymes On T-cell Signmentioning

confidence: 99%

Control of T-Cell Activation and Signaling by Amino-Acid Catabolizing Enzymes

Castellano

Molinier‐Frenkel

2020

Front. Cell Dev. Biol.

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Amino acids are essential for protein synthesis, epigenetic modification through the methylation of histones, and the maintenance of a controlled balance of oxidoreduction via the production of glutathione and are precursors of certain neurotransmitters. T lymphocytes are particularly sensitive to fluctuations in amino acid levels. During evolution, the production of amino-acid catabolizing enzymes by mainly antigen-presenting cells has become a physiological mechanism to control T-cell activation and polarization. The action of these enzymes interferes with TCR and co-stimulation signaling, allowing tuning of the T-cell response. These capacities can be altered in certain pathological conditions, with relevant consequences for the development of disease.

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“…Activation of both mTORC1 and mTORC2 in response to TCR co-stimulation is well established to be PI3K-dependent with AKT being a central mediator of the activating crosstalk between both mTORC complexes ( Fig 8A ) [82, 83]. Since mTORC1 is a critical facilitator of protein synthesis [84], we reasoned that activation of the PI3K-mTORC2-AKT-mTORC1 signaling pathway may contribute to generation of P-TEFb by enabling the translation of the CycT1 subunit which, in line with the P-TEFb biogenesis pathway ( Fig 1A ), is a prerequisite for the subsequent T-loop phosphorylation of CDK9 at both Thr186 and Ser175.…”

Section: Resultsmentioning

confidence: 99%

“…The copyright holder for this preprint (which this version posted April 26, 2021. ; https://doi.org/10.1101/2021.04.26.441433 doi: bioRxiv preprint Activation of both mTORC1 and mTORC2 in response to TCR co-stimulation is well established to be PI3K-dependent with AKT being a central mediator of the activating crosstalk between both mTORC complexes (Fig 8A) [82,83]. Since mTORC1 is a critical facilitator of protein synthesis [84], we reasoned that activation of the PI3K-mTORC2-AKT-mTORC1 signaling pathway may contribute to generation of P-TEFb by enabling the translation of the CycT1 subunit which, in line with the P-TEFb biogenesis pathway (Fig 1A (Rapamycin) or a selective mTOR kinase inhibitor (Torin) that blocks both mTORC1 and mTORC2 activities. Mean fold reductions in TCR-induced P-TEFb expression upon PI3K, mTORC1, and mTORC1/2 inhibition were found to be 2.1, 1.9, and 2.2, respectively (Table 1).…”

Section: Pi3k-mtorc1/2 and Rasgrp1-erk1/2 Are Complementary Pathways That Are Essential For P-tefb Biogenesis And Emergence Of Hiv From Lmentioning

confidence: 99%

Biogenesis of P-TEFb in CD4⁺ T cells to reverse HIV latency is mediated by protein kinase C (PKC)-independent signaling pathways

Mbonye

Leskov

Shukla

et al. 2021

Preprint

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The switch between HIV latency and productive transcription is regulated by an auto-feedback mechanism initiated by the viral trans-activator Tat, which functions to recruit the host transcription elongation factor P-TEFb to proviral HIV. A heterodimeric complex of CDK9 and one of three cyclin T subunits, P-TEFb is expressed at vanishingly low levels in resting memory CD4 + T cells and cellular mechanisms controlling its availability are central to regulation of the emergence of HIV from latency. Using a well-characterized primary T-cell model of HIV latency alongside healthy donor memory CD4 + T cells, we characterized specific T-cell receptor (TCR) signaling pathways that regulate the generation of transcriptionally active P-TEFb, defined as the coordinate expression of cyclin T1 and phospho-Ser175 CDK9. Protein kinase C (PKC) agonists, such as ingenol and prostratin, stimulated active P-TEFb expression and reactivated latent HIV with minimal cytotoxicity, even in the absence of intracellular calcium mobilization with an ionophore. Unexpectedly, inhibition-based experiments demonstrated that PKC agonists and TCR-mobilized diacylglycerol signal through MAP kinases ERK1/2 rather than through PKC to effect the reactivation of both P-TEFb and latent HIV. Single-cell and bulk RNA-seq analyses revealed that of the four known isoforms of the Ras guanine nucleotide exchange factor RasGRP, RasGRP1 is by far the predominantly expressed diacylglycerol-dependent isoform in CD4 + T cells. RasGRP1 should therefore mediate the activation of ERK1/2 via Ras-Raf signaling upon TCR co-stimulation or PKC agonist challenge. Combined inhibition of the PI3K-mTORC2-AKT-mTORC1 pathway and the ERK1/2 activator MEK prior to TCR co-stimulation abrogated active P-TEFb expression and substantially suppressed latent HIV reactivation. Therefore, contrary to prevailing models, the coordinate reactivation of P-TEFb and latent HIV in primary T cells following either TCR co-stimulation or PKC agonist challenge is independent of PKC but rather involves two complementary signaling arms of the TCR cascade, namely, RasGRP1-Ras-Raf-MEK-ERK1/2 and PI3K-mTORC2-AKT-mTORC1.

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

Cited by 121 publications

References 266 publications

Immunometabolism: From basic mechanisms to translation

Immunometabolism: From basic mechanisms to translation

Control of T-Cell Activation and Signaling by Amino-Acid Catabolizing Enzymes

Biogenesis of P-TEFb in CD4⁺ T cells to reverse HIV latency is mediated by protein kinase C (PKC)-independent signaling pathways

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

Cited by 121 publications

References 266 publications

Immunometabolism: From basic mechanisms to translation

Immunometabolism: From basic mechanisms to translation

Control of T-Cell Activation and Signaling by Amino-Acid Catabolizing Enzymes

Biogenesis of P-TEFb in CD4+ T cells to reverse HIV latency is mediated by protein kinase C (PKC)-independent signaling pathways

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Biogenesis of P-TEFb in CD4⁺ T cells to reverse HIV latency is mediated by protein kinase C (PKC)-independent signaling pathways