FOXO1 constrains activation and regulates senescence in CD8 T cells

Delpoux, Arnaud; Marcel, Nimi; Michelini, Rodrigo Hess; Katayama, Carol D.; Allison, Karmel A.; Glass, Christopher K.; Quiñones-Parra, Sergio M.; Murre, Cornelis; Loh, Liyen; Kedzierska, Katherine; Lappas, Martha; Hedrick, Stephen M.; Doedens, Andrew L.

doi:10.1016/j.celrep.2020.108674

Cited by 60 publications

(47 citation statements)

References 105 publications

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“…In terms of T cell exhaustion and the ability of PI3K p110d to control CD8 + effector/memory T cells transition then FOXO1 control of Ctla4 and Slamf6 mRNA could be relevant as these two molecules control T cell exhaustion (26,60,61). However, the role of FOXO1 in enforcing T cell quiescence by controlling expression of Tcf7, Klf2 and AP-1 family transcription factors will also be important in regulating the effector/memory versus senescent fate of CD8 + T cells (50). Moreover, PI3K p110d and FOXO1 control of T cell trafficking, by regulating the expression of key adhesion receptors and chemokine receptors, will also influence CD8 + T cell immune responses in vivo as will PI3K p110d control of the production of inflammatory cytokines and chemokines that recruit and/or regulate innate immune cells.…”

Section: Discussionmentioning

confidence: 99%

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Phosphoinositide 3-Kinase p110 Delta Differentially Restrains and Directs Naïve Versus Effector CD8+ T Cell Transcriptional Programs

et al. 2021

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Phosphoinositide 3-kinase p110 delta (PI3K p110δ) is pivotal for CD8+ T cell immune responses. The current study explores PI3K p110δ induction and repression of antigen receptor and cytokine regulated programs to inform how PI3K p110δ directs CD8+ T cell fate. The studies force a revision of the concept that PI3K p110δ controls metabolic pathways in T cells and reveal major differences in PI3K p110δ regulated transcriptional programs between naïve and effector cytotoxic T cells (CTL). These differences include differential control of the expression of cytolytic effector molecules and costimulatory receptors. Key insights from the work include that PI3K p110δ signalling pathways repress expression of the critical inhibitory receptors CTLA4 and SLAMF6 in CTL. Moreover, in both naïve and effector T cells the dominant role for PI3K p110δ is to restrain the production of the chemokines that orchestrate communication between adaptive and innate immune cells. The study provides a comprehensive resource for understanding how PI3K p110δ uses multiple processes mediated by Protein Kinase B/AKT, FOXO1 dependent and independent mechanisms and mitogen-activated protein kinases (MAPK) to direct CD8+ T cell fate.

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Section: Discussionmentioning

confidence: 99%

“…proteomexchange.org/, PXD025061. ChIP-seq, and ATAC-seq datasets were previously published (50) and deposited to the NCBI GEO/SRA and can be accessed with the identifier GSE163723.…”

Section: Data Availability Statementmentioning

confidence: 99%

Phosphoinositide 3-Kinase p110 Delta Differentially Restrains and Directs Naïve Versus Effector CD8+ T Cell Transcriptional Programs

et al. 2021

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“…4 A–C). Of note, the transcription factor FOXO1 was recently shown to be a negative regulator of glycolysis and T cell fitness 32 , 33 and appeared upregulated upon zinc (Fig. 4 B).…”

Section: Resultsmentioning

confidence: 92%

“…Recently, the transcription factor FOXO1 was reported to be a negative regulator of T cell metabolism, proliferation and effector function 32 , 33 , while MYC is a well-known transcriptional regulator of glycolytic genes in T cells, which is in part controlled by FOXO1 34 , 35 . In our upstream regulator analysis of the DEG controlled by zinc, we detected FOXO1 to be among the most significant upregulated and, inversely, MYC as most significant downregulated transcriptional regulator.…”

Section: Discussionmentioning

confidence: 99%

Ionic mitigation of CD4+ T cell metabolic fitness, Th1 central nervous system autoimmunity and Th2 asthmatic airway inflammation by therapeutic zinc

Krone

Schreiber

et al. 2022

Sci Rep

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T helper (Th) cells provide immunity to pathogens but also contribute to detrimental immune responses during allergy and autoimmunity. Th2 cells mediate asthmatic airway inflammation and Th1 cells are involved in the pathogenesis of multiple sclerosis. T cell activation involves complex transcriptional networks and metabolic reprogramming, which enable proliferation and differentiation into Th1 and Th2 cells. The essential trace element zinc has reported immunomodulatory capacity and high zinc concentrations interfere with T cell function. However, how high doses of zinc affect T cell gene networks and metabolism remained so far elusive. Herein, we demonstrate by means of transcriptomic analysis that zinc aspartate (UNIZINK), a registered pharmaceutical infusion solution with high bioavailability, negatively regulates gene networks controlling DNA replication and the energy metabolism of murine CD3/CD28-activated CD4+ T cells. Specifically, in the presence of zinc, CD4+ T cells show impaired expression of cell cycle, glycolytic and tricarboxylic acid cycle genes, which functionally cumulates in reduced glycolysis, oxidative phosphorylation, metabolic fitness and viability. Moreover, high zinc concentrations impaired nuclear expression of the metabolic transcription factor MYC, prevented Th1 and Th2 differentiation in vitro and reduced Th1 autoimmune central nervous system (CNS) inflammation and Th2 asthmatic airway inflammation induced by house dust mites in vivo. Together, we find that higher zinc doses impair the metabolic fitness of CD4+ T cells and prevent Th1 CNS autoimmunity and Th2 allergy.

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“…It controls various cellular responses, ranging from apoptosis, DNA repair, and metabolism to ROS detoxification and cell proliferation. The sirtuins and FOXO family members play important roles in various aspects of vessel growth, maintenance, and function [ 42 , 43 ]. Among them, some papers indicate that SIRT1, SIRT3, and FOXO1 may be related to fibrosis and inflammation in addition to vascular aging [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

N-acetyl cysteine ameliorates aortic fibrosis by promoting M2 macrophage polarization in aging mice

et al. 2021

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Background: Vascular fibrosis is a universal phenomenon associated with aging, and oxidative stress plays an important role in the genesis of vascular damage in line with the aging process. However, whether antioxidants can ameliorate vascular fibrosis remains unclear. Objectives: The present study was to determine antioxidant N-acetylcysteine (NAC) could ameliorates aortic fibrosis in aging wild-type C57BL/6 mice. Methods : The aortas were harvested from both 12-week and 60-week wild-type mice. The 60-week mice were treated with and without the NAC for 12 weeks starting at the age of 48 weeks. Hematoxylin and eosin (H&E) staining and Masson's trichrome staining of aortic samples were performed, and the levels of reactive oxygen species (ROS), RNA expression of GAPDH, TNF-α, MCP-1, IL-6, IL-10, IL-4, SIRT-1, SIRT-3, FOXO-1, and macrophage polarization were determined. Results: There is a positive relationship between collagen deposition and the M1/M2 macrophage ratio in the aortic wall of aged wild-type C57BL/6 mice. The higher collagen area percentage in the aortas of 60-week-old mice than in 12-week-old mice was reversed by NAC. NAC could not impact the total number of macrophages, but partly promoted M2 macrophage polarization. By performing qRT-PCR using aortic samples from these mice, we identified that SIRT-1, SIRT-3, FOXO-1 could be somehow responsible for aging-related fibrosis. Conclusions: NAC ameliorates aortic fibrosis in aging wild type mice partly by promoting M2 macrophage polarization.

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FOXO1 constrains activation and regulates senescence in CD8 T cells

Abstract: Highlights d FOXO1 opposes senescence and the effector program in T cells d FOXO1 directly binds genomic loci of AP-1 subunits and AP-1 repressor BACH2 d Age and progressive cellular differentiation each decrease FOXO1 and increase AP-1

Cited by 60 publications

References 105 publications

Phosphoinositide 3-Kinase p110 Delta Differentially Restrains and Directs Naïve Versus Effector CD8+ T Cell Transcriptional Programs

Phosphoinositide 3-Kinase p110 Delta Differentially Restrains and Directs Naïve Versus Effector CD8+ T Cell Transcriptional Programs

Ionic mitigation of CD4+ T cell metabolic fitness, Th1 central nervous system autoimmunity and Th2 asthmatic airway inflammation by therapeutic zinc

N-acetyl cysteine ameliorates aortic fibrosis by promoting M2 macrophage polarization in aging mice

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