scholarly journals Epigenetic modification of the PD-1 (Pdcd1) promoter in effector CD4+ T cells tolerized by peptide immunotherapy

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Rhoanne C McPherson ◽  
Joanne E Konkel ◽  
Catriona T Prendergast ◽  
John P Thomson ◽  
Raffaele Ottaviano ◽  
...  
Keyword(s):  
T Cells ◽  
Epigenetic Modification ◽  
Dna Hypomethylation ◽  
Peptide Immunotherapy ◽  
Tet Proteins ◽  
Genes Encoding ◽  
Inhibitory Molecule ◽  
Immune Pathology ◽  
Cell Expression ◽  
Cytosine Demethylation

Clinically effective antigen-based immunotherapy must silence antigen-experienced effector T cells (Teff) driving ongoing immune pathology. Using CD4+ autoimmune Teff cells, we demonstrate that peptide immunotherapy (PIT) is strictly dependent upon sustained T cell expression of the co-inhibitory molecule PD-1. We found high levels of 5-hydroxymethylcytosine (5hmC) at the PD-1 (Pdcd1) promoter of non-tolerant T cells. 5hmC was lost in response to PIT, with DNA hypomethylation of the promoter. We identified dynamic changes in expression of the genes encoding the Ten-Eleven-Translocation (TET) proteins that are associated with the oxidative conversion 5-methylcytosine and 5hmC, during cytosine demethylation. We describe a model whereby promoter demethylation requires the co-incident expression of permissive histone modifications at the Pdcd1 promoter together with TET availability. This combination was only seen in tolerant Teff cells following PIT, but not in Teff that transiently express PD-1. Epigenetic changes at the Pdcd1 locus therefore determine the tolerizing potential of TCR-ligation.

scholarly journals Author response: Epigenetic modification of the PD-1 (Pdcd1) promoter in effector CD4+ T cells tolerized by peptide immunotherapy

2014 ◽  
Author(s):  
Rhoanne C McPherson ◽  
Joanne E Konkel ◽  
Catriona T Prendergast ◽  
John P Thomson ◽  
Raffaele Ottaviano ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Epigenetic Modification ◽  
Author Response ◽  
Peptide Immunotherapy

scholarly journals Author Correction: Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH

Nature ◽  
2021 ◽  
Author(s):  
Michael Dudek ◽  
Dominik Pfister ◽  
Sainitin Donakonda ◽  
Pamela Filpe ◽  
Annika Schneider ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Immune Pathology

scholarly journals The chromosomal protein SMCHD1 regulates DNA methylation and the 2c-like state of embryonic stem cells by antagonizing TET proteins

2021 ◽  
Vol 7 (4) ◽  
pp. eabb9149
Author(s):  
Zhijun Huang ◽  
Jiyoung Yu ◽  
Wei Cui ◽  
Benjamin K. Johnson ◽  
Kyunggon Kim ◽  
...  
Keyword(s):  
Es Cells ◽  
Embryonic Stem ◽  
Homeobox Gene ◽  
Dna Demethylation ◽  
Chromosomal Protein ◽  
Dna Hypomethylation ◽  
Tet Proteins ◽  
Target Sites ◽  
Structural Maintenance Of Chromosomes ◽  
Hinge Domain

5-Methylcytosine (5mC) oxidases, the ten-eleven translocation (TET) proteins, initiate DNA demethylation, but it is unclear how 5mC oxidation is regulated. We show that the protein SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1) is found in complexes with TET proteins and negatively regulates TET activities. Removal of SMCHD1 from mouse embryonic stem (ES) cells induces DNA hypomethylation, preferentially at SMCHD1 target sites and accumulation of 5-hydroxymethylcytosine (5hmC), along with promoter demethylation and activation of the Dux double-homeobox gene. In the absence of SMCHD1, ES cells acquire a two-cell (2c) embryo–like state characterized by activation of an early embryonic transcriptome that is substantially imposed by Dux. Using Smchd1/Tet1/Tet2/Tet3 quadruple-knockout cells, we show that DNA demethylation, activation of Dux, and other genes upon SMCHD1 loss depend on TET proteins. These data identify SMCHD1 as an antagonist of the 2c-like state of ES cells and of TET-mediated DNA demethylation.

scholarly journals Simultaneous deletion of the methylcytosine oxidases Tet1 and Tet3 increases transcriptome variability in early embryogenesis

2015 ◽  
Vol 112 (31) ◽  
pp. E4236-E4245 ◽  
Author(s):  
Jinsuk Kang ◽  
Matthias Lienhard ◽  
William A. Pastor ◽  
Ashu Chawla ◽  
Mark Novotny ◽  
...  
Keyword(s):  
Single Cells ◽  
Cholesterol Biosynthesis ◽  
Early Embryogenesis ◽  
Dna Demethylation ◽  
Cell Stage ◽  
Tet Proteins ◽  
Genes Encoding ◽  
Variable Gene ◽  
Intracellular Pathways ◽  
Tet Enzymes

Dioxygenases of the TET (Ten-Eleven Translocation) family produce oxidized methylcytosines, intermediates in DNA demethylation, as well as new epigenetic marks. Here we show data suggesting that TET proteins maintain the consistency of gene transcription. Embryos lacking Tet1 and Tet3 (Tet1/3 DKO) displayed a strong loss of 5-hydroxymethylcytosine (5hmC) and a concurrent increase in 5-methylcytosine (5mC) at the eight-cell stage. Single cells from eight-cell embryos and individual embryonic day 3.5 blastocysts showed unexpectedly variable gene expression compared with controls, and this variability correlated in blastocysts with variably increased 5mC/5hmC in gene bodies and repetitive elements. Despite the variability, genes encoding regulators of cholesterol biosynthesis were reproducibly down-regulated in Tet1/3 DKO blastocysts, resulting in a characteristic phenotype of holoprosencephaly in the few embryos that survived to later stages. Thus, TET enzymes and DNA cytosine modifications could directly or indirectly modulate transcriptional noise, resulting in the selective susceptibility of certain intracellular pathways to regulation by TET proteins.

scholarly journals Mouse Models of Antigen Presentation in Hematopoietic Stem Cell Transplantation

2021 ◽  
Vol 12 ◽  
Author(s):  
Motoko Koyama ◽  
Geoffrey R. Hill
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Mouse Models ◽  
Major Complication ◽  
Hematopoietic Stem ◽  
Curative Therapy ◽  
Donor T Cells ◽  
Immune Pathology

Allogeneic stem cell transplantation (alloSCT) is a curative therapy for hematopoietic malignancies. The therapeutic effect relies on donor T cells and NK cells to recognize and eliminate malignant cells, known as the graft-versus-leukemia (GVL) effect. However, off target immune pathology, known as graft-versus-host disease (GVHD) remains a major complication of alloSCT that limits the broad application of this therapy. The presentation of recipient-origin alloantigen to donor T cells is the primary process initiating GVHD and GVL. Therefore, the understanding of spatial and temporal characteristics of alloantigen presentation is pivotal to attempts to separate beneficial GVL effects from detrimental GVHD. In this review, we discuss mouse models and the tools therein, that permit the quantification of alloantigen presentation after alloSCT.

scholarly journals Mamu-B*17+Rhesus Macaques Vaccinated withenv,vif, andnefManifest Early Control of SIVmac239 Replication

2018 ◽  
Vol 92 (16) ◽  
Author(s):  
Mauricio A. Martins ◽  
Damien C. Tully ◽  
Núria Pedreño-Lopez ◽  
Benjamin von Bredow ◽  
Matthias G. Pauthner ◽  
...  
Keyword(s):  
T Cells ◽  
Rhesus Macaques ◽  
Chronic Phase ◽  
Virologic Suppression ◽  
Mhc I ◽  
Immunodeficiency Virus ◽  
Genes Encoding ◽  
Siv Infection ◽  
Group 2 ◽  
Group 1

ABSTRACTCertain major histocompatibility complex class I (MHC-I) alleles are associated with spontaneous control of viral replication in human immunodeficiency virus (HIV)-infected people and simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs). These cases of “elite” control of HIV/SIV replication are often immune-mediated, thereby providing a framework for studying anti-lentiviral immunity. In this study, we examined how vaccination impacts SIV replication in RMs expressing the MHC-I alleleMamu-B*17. Approximately 21% ofMamu-B*17+and 50% ofMamu-B*08+RMs control chronic-phase viremia after SIVmac239 infection. Because CD8+T cells targeting Mamu-B*08-restricted SIV epitopes have been implicated in virologic suppression inMamu-B*08+RMs, we investigated whether this might also be true forMamu-B*17+RMs. Two groups ofMamu-B*17+RMs were vaccinated with genes encoding Mamu-B*17-restricted epitopes in Vif and Nef. These genes were delivered by themselves (group 1) or together withenv(group 2). Group 3 included MHC-I-matched RMs and served as the control group. Surprisingly, the group 1 vaccine regimen had little effect on viral replication compared to group 3, suggesting that unlikeMamu-B*08+RMs, preexisting SIV-specific CD8+T cells alone do not facilitate long-term virologic suppression inMamu-B*17+RMs. Remarkably, however, 5/8 group 2 vaccinees controlled viremia to <15 viral RNA copies/ml soon after infection. No serological neutralizing activity against SIVmac239 was detected in group 2, although vaccine-elicited gp140-binding antibodies correlated inversely with nadir viral loads. Collectively, these data shed new light on the unique mechanism of elite control inMamu-B*17+RMs and implicate vaccine-induced, nonneutralizing anti-Env antibodies in the containment of immunodeficiency virus infection.IMPORTANCEA better understanding of the immune correlates of protection against HIV might facilitate the development of a prophylactic vaccine. Therefore, we investigated simian immunodeficiency virus (SIV) infection outcomes in rhesus macaques expressing the major histocompatibility complex class I alleleMamu-B*17. Approximately 21% ofMamu-B*17+macaques spontaneously controlled chronic phase viremia after SIV infection, an effect that may involve CD8+T cells targeting Mamu-B*17-restricted SIV epitopes. We vaccinatedMamu-B*17+macaques with genes encoding immunodominant epitopes in Vif and Nef alone (group 1) or together withenv(group 2). Although neither vaccine regimen prevented SIV infection, 5/8 group 2 vaccinees controlled viremia to below detection limits shortly after infection. This outcome, which was not observed in group 1, was associated with vaccine-induced, nonneutralizing Env-binding antibodies. Together, these findings suggest a limited contribution of Vif- and Nef-specific CD8+T cells for virologic control inMamu-B*17+macaques and implicate anti-Env antibodies in containment of SIV infection.

scholarly journals Progressive Immunodeficiency with Gradual Depletion of B and CD4+ T Cells in Immunodeficiency, Centromeric Instability and Facial Anomalies Syndrome 2 (ICF2)

Diseases ◽  
2019 ◽  
Vol 7 (2) ◽  
pp. 34 ◽  
Author(s):  
Georgios Sogkas ◽  
Natalia Dubrowinskaja ◽  
Anke K. Bergmann ◽  
Jana Lentes ◽  
Tim Ripperger ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Late Onset ◽  
Epigenetic Modification ◽  
Primary Immunodeficiency Disorder ◽  
Hematopoietic Stem ◽  
Facial Anomalies ◽  
Immunodeficiency Disorder ◽  
Centromeric Instability ◽  
Tract Infections

Immunodeficiency, centromeric instability and facial anomalies syndrome 2 (ICF2) is a rare autosomal recessive primary immunodeficiency disorder. So far, 27 patients have been reported. Here, we present three siblings with ICF2 due to a homozygous ZBTB24 gene mutation (c.1222 T>G, p. (Cys408Gly)). Immune deficiency in these patients ranged from late-onset combined immunodeficiency (CID) with severe respiratory tract infections and recurrent shingles to asymptomatic selective antibody deficiency. Evident clinical heterogeneity manifested despite a common genetic background, suggesting the pathogenic relevance of epigenetic modification. Immunological follow-up reveals a previously unidentified gradual depletion of B and CD4+ T cells in all three presented patients with transition of a common variable immunodeficiency (CVID)-like disease to late-onset-CID in one of them. Considering all previously published cases with ICF2, we identify inadequate antibody responses to vaccines and reduction in CD27+ memory B cells as prevalent immunological traits. High mortality among ICF2 patients (20%) together with the progressive course of immunodeficiency suggest that hematopoietic stem cell transplantation (HSCT) should be considered as a treatment option in due time.

scholarly journals SIR2 Expression Noise Can Generate Heterogeneity in Viability but Does Not Affect Cell-to-Cell Epigenetic Silencing of Subtelomeric URA3 in Yeast

2020 ◽  
Vol 10 (9) ◽  
pp. 3435-3443
Author(s):  
Jian Liu ◽  
Laureline Mosser ◽  
Catherine Botanch ◽  
Jean-Marie François ◽  
Jean-Pascal Capp
Keyword(s):  
Gene Expression ◽  
Saccharomyces Cerevisiae ◽  
Epigenetic Modification ◽  
Epigenetic Silencing ◽  
Cell Heterogeneity ◽  
Gene Expression Noise ◽  
Expression Noise ◽  
Cell Expression ◽  
Cell To Cell Variability ◽  
Epigenetic Processes

Abstract Chromatin structure clearly modulates gene expression noise, but the reverse influence has never been investigated, namely how the cell-to-cell expression heterogeneity of chromatin modifiers may generate variable rates of epigenetic modification. Sir2 is a well-characterized histone deacetylase of the Sirtuin family. It strongly influences chromatin silencing, especially at telomeres, subtelomeres and rDNA. This ability to influence epigenetic landscapes makes it a good model to study the largely unexplored interplay between gene expression noise and other epigenetic processes leading to phenotypic diversification. Here, we addressed this question by investigating whether noise in the expression of SIR2 was associated with cell-to-cell heterogeneity in the frequency of epigenetic silencing at subtelomeres in Saccharomyces cerevisiae. Using cell sorting to isolate subpopulations with various expression levels, we found that heterogeneity in the cellular concentration of Sir2 does not lead to heterogeneity in the epigenetic silencing of subtelomeric URA3 between these subpopulations. We also noticed that SIR2 expression noise can generate cell-to-cell variability in viability, with lower levels being associated with better viability. This work shows that SIR2 expression fluctuations are not sufficient to generate cell-to-cell heterogeneity in the epigenetic silencing of URA3 at subtelomeres in Saccharomyces cerevisiae but can strongly affect cellular viability.

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