Transcriptional insights into the CD8+ T cell response to infection and memory T cell formation

Best, J Adam; Blair, David A.; Knell, Jamie; Yang, Edward; Mayya, Viveka; Doedens, Andrew L.; Dustin, Michael L.; Goldrath, Ananda W.

doi:10.1038/ni.2536

Cited by 298 publications

(379 citation statements)

References 35 publications

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“…While rapid changes in gene expression have been described in na€ ıve T cells differentiating to effector and memory cells, little consensus exists on the methylation alterations that accompany these early events. 10,13 Our observations at 16 h are consistent with previously published data studying CD4 T cells undergoing in vitro activation with CD3 and CD28 antibodies. 6 Further studies are necessary to determine if the lack of early kinetic change in methylation is due to steps involving active TET-mediated hydroxymethylation or a passive dilution and lack of methylation maintenance.…”

Section: Long-term But Not Short-term Activation Leads To Methylome Rsupporting

confidence: 82%

“…9 Less understood is the extent to which stable and heritable changes in DNA methylation might be produced during immune activation within cells of a common lineage identity. Although transcriptomic studies implicate genome wide alterations in gene expression during pathogen-and cytokine-induced immune activation in different cell types, [10][11][12][13][14] the exact role of DNA methylation in the genesis of these effects is not known. However, a few individual loci have been studied intensively.…”

Section: Foxp3mentioning

confidence: 99%

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The DNA methylation profile of activated human natural killer cells

et al. 2016

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Natural killer (NK) cells are now recognized to exhibit characteristics akin to cells of the adaptive immune system. The generation of adaptive memory is linked to epigenetic reprogramming including alterations in DNA methylation. The study herein found reproducible genome wide DNA methylation changes associated with human NK cell activation. Activation led predominately to CpG hypomethylation (81% of significant loci). Bioinformatics analysis confirmed that non-coding and gene-associated differentially methylated sites (DMS) are enriched for immune related functions (i.e., immune cell activation). Known DNA methylation-regulated immune loci were also identified in activated NK cells (e.g., TNFA, LTA, IL13, CSF2). Twenty-one loci were designated high priority and further investigated as potential markers of NK activation. BHLHE40 was identified as a viable candidate for which a droplet digital PCR assay for demethylation was developed. The assay revealed high demethylation in activated NK cells and low demethylation in na€ ıve NK, T-and B-cells. We conclude the NK cell methylome is plastic with potential for remodeling. The differentially methylated region signature of activated NKs revealed similarities with T cell activation, but also provided unique biomarker candidates of NK activation, which could be useful in epigenome-wide association studies to interrogate the role of NK subtypes in global methylation changes associated with exposures and/or disease states.

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Section: Long-term But Not Short-term Activation Leads To Methylome Rsupporting

confidence: 82%

Section: Foxp3mentioning

confidence: 99%

The DNA methylation profile of activated human natural killer cells

et al. 2016

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“…In line with previous studies in memory T cells (32), in vitrogenerated Ag-experienced CD8 + T cells express transcripts for TLR2, TLR3, TLR5, TLR7, and TLR9 (Fig. 1A).…”

Section: Cd8supporting

confidence: 72%

TLR-Mediated Innate Production of IFN-γ by CD8+ T Cells Is Independent of Glycolysis

Salerno

Guislain

Cansever

et al. 2016

The Journal of Immunology

120

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CD8+ T cells can respond to unrelated infections in an Ag-independent manner. This rapid innate-like immune response allows Ag-experienced T cells to alert other immune cell types to pathogenic intruders. In this study, we show that murine CD8+ T cells can sense TLR2 and TLR7 ligands, resulting in rapid production of IFN-γ but not of TNF-α and IL-2. Importantly, Ag-experienced T cells activated by TLR ligands produce sufficient IFN-γ to augment the activation of macrophages. In contrast to Ag-specific reactivation, TLR-dependent production of IFN-γ by CD8+ T cells relies exclusively on newly synthesized transcripts without inducing mRNA stability. Furthermore, transcription of IFN-γ upon TLR triggering depends on the activation of PI3K and serine-threonine kinase Akt, and protein synthesis relies on the activation of the mechanistic target of rapamycin. We next investigated which energy source drives the TLR-induced production of IFN-γ. Although Ag-specific cytokine production requires a glycolytic switch for optimal cytokine release, glucose availability does not alter the rate of IFN-γ production upon TLR-mediated activation. Rather, mitochondrial respiration provides sufficient energy for TLR-induced IFN-γ production. To our knowledge, this is the first report describing that TLR-mediated bystander activation elicits a helper phenotype of CD8+ T cells. It induces a short boost of IFN-γ production that leads to a significant but limited activation of Ag-experienced CD8+ T cells. This activation suffices to prime macrophages but keeps T cell responses limited to unrelated infections.

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“…For simplicity, the Zeb2 flox/flox ; GzmB-cre + mice will be referred to as Zeb2 −/− mice and Zeb2 flox/flox ; GzmB-cre − or Zeb +/+ ; GzmB-cre + littermate controls will be referred to as WT mice. It was important to use a conditional knock-out strategy because Zeb2 −/− mice show embryonic lethality and Zeb2 is expressed in many cell types, including hematopoietic stem cells, NK cells, monocytes, and mast cells (Tylzanowski et al, 2003;van Grunsven et al, 2006;Goossens et al, 2011;Barbu et al, 2012;Best et al, 2013). Zeb2 was efficiently deleted in ∼85-90% of the polyclonal CD44 hi CD8 + T cells using this system (unpublished data).…”

Section: Res Ults Zeb2 Is Expressed In Klrg1 Hi Cd8 + T Cells In a T-mentioning

confidence: 99%

The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infection

Dominguez¹,

Guan²,

Marshall³

et al. 2015

J Cell Biol

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Transcriptional insights into the CD8+ T cell response to infection and memory T cell formation

Cited by 298 publications

References 35 publications

The DNA methylation profile of activated human natural killer cells

The DNA methylation profile of activated human natural killer cells

TLR-Mediated Innate Production of IFN-γ by CD8+ T Cells Is Independent of Glycolysis

The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infection

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