A genome-wide regulatory network identifies key transcription factors for memory CD8+ T-cell development

Hu, Guangan; Chen, Jianzhu

doi:10.1038/ncomms3830

Cited by 105 publications

(113 citation statements)

References 62 publications

(70 reference statements)

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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%

“…51 Additional roles of BHLHE40 and other differentially methylated transcription factors can be found in Table 3. 13,[52][53][54][55][56][57] Based on its role in T and NKT development and apparent significance in NK cell activation, several ddPCR assays for quantitating BHLHE40 demethylation were designed and evaluated. Cloning and bisulfite sequencing revealed broad and heterogeneous demethylation within the exon 5 region.…”

Section: Transcription Factors: Bhlhe40 Zbtb32/fazf Nfatc1 Bach2mentioning

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%

Section: Transcription Factors: Bhlhe40 Zbtb32/fazf Nfatc1 Bach2mentioning

confidence: 99%

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The DNA methylation profile of activated human natural killer cells

et al. 2016

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“…However, no significant changes in Bhlhe40 mRNA expression were observed in iNKT cells of mice subjected to dark/light cycles, suggesting that the functions of Bhlhe40 in iNKT cells are independent of the circadian rhythm. Bhlhe40 was shown to control various functions of T cells, such as turning of naïve CD8 + T cells into memory ones, cytokine productions, or tumor infiltration, in a circadian rhythm-independent manner (43)(44)(45). Similarly, in this study, we report a previously unidentified function for Bhlhe40 as an enhancer of IFN-γ production in iNKT cells that is also independent of the circadian rhythm.…”

Section: Bhlhe40 -/-Inktsupporting

confidence: 51%

Transcriptional regulator Bhlhe40 works as a cofactor of T-bet in the regulation of IFN-γ production iniNKT cells

Kanda

Yamanaka

Kojo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Invariant natural killer T (iNKT) cells are a subset of innate-like T cells that act as important mediators of immune responses. In particular, iNKT cells have the ability to immediately produce large amounts of IFN-γ upon activation and thus initiate immune responses in various pathological conditions. However, molecular mechanisms that control IFN-γ production in iNKT cells are not fully understood. Here, we report that basic helix-loop-helix transcription factor family, member e40 (Bhlhe40), is an important regulator for IFN-γ production in iNKT cells. Bhlhe40 is highly expressed in stage 3 thymic iNKT cells and iNKT1 subsets, and the level of Bhlhe40 mRNA expression is correlated with Ifng mRNA expression in the resting state. Although Bhlhe40-deficient mice show normal iNKT cell development, Bhlhe40-deficient iNKT cells show significant impairment of IFN-γ production and antitumor effects. Bhlhe40 alone shows no significant effects on Ifng promoter activities but contributes to enhance T-box transcription factor Tbx21 (T-bet)-mediated Ifng promoter activation. Chromatin immunoprecipitation analysis revealed that Bhlhe40 accumulates in the T-box region of the Ifng locus and contributes to histone H3-lysine 9 acetylation of the Ifng locus, which is impaired without T-bet conditions. These results indicate that Bhlhe40 works as a cofactor of T-bet for enhancing IFN-γ production in iNKT cells.

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“…This may be attributed to feedback regulations due to close interaction of the transcription factors involved. 39 …”

Section: Discussionmentioning

confidence: 99%

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8⁺ T cells for adoptive immunotherapy

Mousset

Hobo

et al. 2018

OncoImmunology

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Adoptive T cell therapy has shown clinical potential for patients with cancer, though effective treatment is dependent on longevity and potency of the exploited tumor-reactive T cells. Previously, we showed that ex vivo inhibition of AKT using the research compound Akt-inhibitor VIII retained differentiation and improved functionality of minor histocompatibility antigen (MiHA)-specific CD8+ T cells. Here, we compared a panel of clinically applicable AKT-inhibitors with an allosteric or adenosine triphosphate-competitive mode of action. We analyzed phenotype, functionality, metabolism and transcriptome of AKT-inhibited CD8+ T cells using different T cell activation models. Most inhibitors facilitated T cell expansion while preserving an early memory phenotype, reflected by maintenance of CD62L, CCR7 and CXCR4 expression. Moreover, transcriptome profiling revealed that AKT-inhibited CD8+ T cells clustered closely to naturally occurring stem cell-memory CD8+ T cells, while control T cells resembled effector-memory T cells. Interestingly, AKT-inhibited CD8+ T cells showed enrichment of hypoxia-associated genes, which was consistent with enhanced glycolytic function. Notably, AKT-inhibition during MiHA-specific CD8+ T cell priming uncoupled preservation of early memory differentiation from ex vivo expansion. Furthermore, AKT-inhibited MiHA-specific CD8+ T cells showed increased polyfunctionality with co-secretion of IFN-γ and IL-2 upon antigen recall. Together, these data demonstrate that AKT-inhibitors with different modality of action promote the ex vivo generation of stem cell memory-like CD8+ T cells with a unique metabolic profile and retained polyfunctionality. Akt-inhibitor VIII and GDC-0068 outperformed other inhibitors, and are therefore promising candidates for ex vivo generation of superior tumor-reactive T cells for adoptive immunotherapy in cancer patients.

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A genome-wide regulatory network identifies key transcription factors for memory CD8+ T-cell development

Cited by 105 publications

References 62 publications

The DNA methylation profile of activated human natural killer cells

The DNA methylation profile of activated human natural killer cells

Transcriptional regulator Bhlhe40 works as a cofactor of T-bet in the regulation of IFN-γ production iniNKT cells

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8⁺ T cells for adoptive immunotherapy

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A genome-wide regulatory network identifies key transcription factors for memory CD8+ T-cell development

Cited by 105 publications

References 62 publications

The DNA methylation profile of activated human natural killer cells

The DNA methylation profile of activated human natural killer cells

Transcriptional regulator Bhlhe40 works as a cofactor of T-bet in the regulation of IFN-γ production iniNKT cells

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8+ T cells for adoptive immunotherapy

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Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8⁺ T cells for adoptive immunotherapy