cAMP Responsive Element Modulator (CREM) α Mediates Chromatin Remodeling of CD8 during the Generation of CD3+CD4−CD8− T Cells

Hedrich, Christian M.; Crispín, José C.; Rauen, Thomas; Ioannidis, Christina; Koga, Tomohiro; Rodríguez-Rodríguez, Noé; Apostolidis, Sokratis A.; Kyttaris, Vasileios C.; Tsokos, George C.

doi:10.1074/jbc.m113.523605

Cited by 69 publications

(56 citation statements)

References 31 publications

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“…CREMα is a transcription factor that directly silences CD8 expression by transrepression of a region syntenic to CD8B in mice [14]. In addition, CREMα induces epigenetic remodeling of CD8A and CD8B to silence expression [9]. We showed increased DNA methylation of CD8A and CD8B in DN compared to CD8+ T cells in human, consistent with previous reports.…”

Section: Discussionsupporting

confidence: 90%

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The DNA methylation signature of human TCRαβ+CD4−CD8− double negative T cells reveals CG demethylation and a unique epigenetic architecture permissive to a broad stimulatory immune response

Renauer

Coit

Sawalha

2015

Clinical Immunology

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T cell receptor (TCR) αβ+CD4−CD8− double negative T cells represent a rare T cell subset implicated in the pathogenesis of several autoimmune diseases. We investigated the DNA methylation signature of double negative T cells to gain insight into the epigenetic architecture of peripheral blood primary human double negative T cells compared to autologous CD4+ and CD8+ T cells. We identified 2984 CG sites across the genome with unique loss of DNA methylation in double negative T cells, and showed significant reduction in mRNA expression of DNA methyltransferases DNMT1, DNMT3A, and DNMT3B. DNA methylation was increased in CD8A/CD8B and CD4 consistent with epigenetic repression of both the CD8 and CD4 genetic loci in double negative T cells. We show a consistent increase in non-CG methylation in double negative T cells, a finding suggestive of pluripotency. Network analyses indicate a strong relationship between double negative T cells and functions related to cell –cell interaction, cell adhesion, and cell activation pathways. Our data also suggest a robust pro-inflammatory epigenetic signature in double negative T cells, consistent with a transcriptional permissiveness in key inflammatory cytokines including IFNγ, IL-17F, IL-12B, IL-5, IL-18, TNFSF11 (RANKL), and TNFSF13B (BLYS or BAFF). These findings highlight an epigenetic basis for a role of double negative T cells in autoimmunity.

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Section: Discussionsupporting

confidence: 90%

“…Importantly, DNA methylation regulates cytokine and transcription factor expression which can determine immune responses and, in CD4+ T cells, differentiation into effector T cell subsets [8]. Further, CREMα-mediated epigenetic remodeling and silencing of CD8 has been recently demonstrated to result in DN T cell expansion [9]. …”

Section: Introductionmentioning

confidence: 99%

The DNA methylation signature of human TCRαβ+CD4−CD8− double negative T cells reveals CG demethylation and a unique epigenetic architecture permissive to a broad stimulatory immune response

Renauer

Coit

Sawalha

2015

Clinical Immunology

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“…It has been proposed that the production of IL-12 by kidney tubular cells of MRL-Fas lpr mice further promotes the recruitment of multiple T cell populations such as CD4 1 , CD8 1 and B220 1 CD4 2 CD8 2 T cells to this organ [27]. Interestingly, this latter population, known as double-negative (DN) T cells, is also present in human autoimmune syndromes [28,29]. This T cell subpopulation infiltrates kidneys, produces IFN-g and contributes to cause renal damage in MRL-Fas lpr lupus mice [26].…”

Section: Introductionmentioning

confidence: 99%

Carbon monoxide inhibits T cell activation in target organs during systemic lupus erythematosus

Mackern-Oberti

Obreque

Méndez

et al. 2015

Clinical and Experimental Immunology

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SummarySystemic lupus erythematosus is characterized by the presence of circulating anti-nuclear antibodies (ANA) and systemic damage that includes nephritis, haematological manifestations and pulmonary compromise, among others. Although major progress has been made in elucidating the molecular mechanisms responsible for autoimmunity, current therapies for lupus have not improved considerably. Because the exposure of carbon monoxide (CO) has been shown to display beneficial immunoregulatory properties in different immune-mediated diseases, we investigated whether CO therapy improves lupus-related kidney injury in lupus mice. MRL-Fas lpr lupus mice were exposed to CO and disease progression was evaluated. ANA, leucocyteinfiltrating populations in spleen, kidney and lung and kidney lesions, were measured. CO therapy significantly decreased the frequency of activated B220 1 CD4 2 CD8 2 T cells in kidneys and lungs, as well as serum levels of ANA. Furthermore, we observed that CO therapy reduced kidney injury by decreasing proliferative glomerular damage and immune complexes deposition, decreased proinflammatory cytokine production and finally delayed the impairment of kidney function. CO exposure ameliorates kidney and lung leucocyte infiltration and delays kidney disease in MRLFas lpr lupus mice. Our data support the notion that CO could be explored as a potential new therapy for lupus nephritis.

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“…This study suggests which molecular substrates might participate in the regulation of these processes. To date the roles of cAMP/PKA signaling are even less well defined for most of the other biological processes implicated, such as chromatin remodeling (85)(86)(87) and chromosomal segregation. Again, the phosphopeptides that map to these processes should be a good place to start mechanistic studies of cAMP/PDE effects on these processes.…”

Section: Biological Processes Regulated By Different Pde-regulatedmentioning

confidence: 99%

Analyses of PDE-regulated phosphoproteomes reveal unique and specific cAMP-signaling modules in T cells

Beltejar

Lau

Golkowski

et al. 2017

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

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Specific functions for different cyclic nucleotide phosphodiesterases (PDEs) have not yet been identified in most cell types. Conventional approaches to study PDE function typically rely on measurements of global cAMP, general increases in cAMP-dependent protein kinase (PKA), or the activity of exchange protein activated by cAMP (EPAC). Although newer approaches using subcellularly targeted FRET reporter sensors have helped define more compartmentalized regulation of cAMP, PKA, and EPAC, they have limited ability to link this regulation to downstream effector molecules and biological functions. To address this problem, we have begun to use an unbiased mass spectrometry-based approach coupled with treatment using PDE isozyme-selective inhibitors to characterize the phosphoproteomes of the functional pools of cAMP/PKA/EPAC that are regulated by specific cAMP-PDEs (the PDE-regulated phosphoproteomes). In Jurkat cells we find multiple, distinct PDE-regulated phosphoproteomes that can be defined by their responses to different PDE inhibitors. We also find that little phosphorylation occurs unless at least two different PDEs are concurrently inhibited in these cells. Moreover, bioinformatics analyses of these phosphoproteomes provide insight into the unique functional roles, mechanisms of action, and synergistic relationships among the different PDEs that coordinate cAMP-signaling cascades in these cells. The data strongly suggest that the phosphorylation of many different substrates contributes to cAMP-dependent regulation of these cells. The findings further suggest that the approach of using selective, inhibitor-dependent phosphoproteome analysis can provide a generalized methodology for understanding the roles of different PDEs in the regulation of cyclic nucleotide signaling.

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cAMP Responsive Element Modulator (CREM) α Mediates Chromatin Remodeling of CD8 during the Generation of CD3+CD4−CD8− T Cells

Abstract: Background: Expanded double negative T cells in systemic lupus erythematosus (SLE) originate from CD8 ϩ T cells.

Cited by 69 publications

References 31 publications

The DNA methylation signature of human TCRαβ+CD4−CD8− double negative T cells reveals CG demethylation and a unique epigenetic architecture permissive to a broad stimulatory immune response

The DNA methylation signature of human TCRαβ+CD4−CD8− double negative T cells reveals CG demethylation and a unique epigenetic architecture permissive to a broad stimulatory immune response

Carbon monoxide inhibits T cell activation in target organs during systemic lupus erythematosus

Analyses of PDE-regulated phosphoproteomes reveal unique and specific cAMP-signaling modules in T cells

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