scholarly journals Dietary Sodium Restriction Results in Tissue-Specific Changes in DNA Methylation in Humans

Hypertension ◽  
2021 ◽  
Author(s):  
Srividya Kidambi ◽  
Xiaoqing Pan ◽  
Chun Yang ◽  
Pengyuan Liu ◽  
Michelle L. Roberts ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
T Cell ◽  
Vascular Function ◽  
Dietary Sodium ◽  
Flow Mediated Dilation ◽  
Sodium Restriction ◽  
Differentially Methylated Regions ◽  
Dietary Effects ◽  
Tissue Specific

Dietary sodium affects blood pressure (BP) and vascular function. Animal studies suggest epigenetic changes (eg, DNA methylation) are involved. We hypothesized that sodium restriction induces methylation changes in T cells and arterioles in humans. Fifty subjects (49% women) were placed on 1200-mg sodium/day diet for 2 weeks. BP and brachial artery flow-mediated dilation were evaluated. Methylation sequencing (pre- and post-diet) was performed on T-cell (n=50) and biopsied arteriolar (n=10) DNA. RNA sequencing was also performed on arterioles (n=11). Over 2 weeks, mean sodium consumption was 946 mg/day. Average BP reductions after low-sodium intake were −8±13/−4±9 mm Hg ( P <0.001). Flow-mediated dilation improved (5.8±2.9% to 6.8±3.4%; P =0.03). T-cell DNA was substantially more methylated than arterioles. The differentially methylated regions (false discovery rate, <0.05) identified in T cells and arterioles after sodium restriction were located in 117 and 71 genes, respectively. Four genes were identified in both T cells and arterioles ( P =0.009 for the overlap). The dietary effects on methylation in several DNA regions were associated with dietary effects on BP. Several differentially expressed genes in arterioles contained differentially methylated regions at the significance level of P <0.05. In addition, 46 genes contained differentially methylated regions in both human and SS/Mcw rat T cells ( P =0.03 for the overlap). Sodium restriction significantly affected DNA methylation in T cells and arterioles, some of which are associated with BP. Methylation patterns and sodium effects on methylation are largely tissue specific but also have overlaps between tissues and species. These findings may lead to better understanding of dietary sodium interactions with cellular processes and, therefore, novel therapeutic targets.

scholarly journals Differential Roles of IL-2–Inducible T Cell Kinase-Mediated TCR Signals in Tissue-Specific Localization and Maintenance of Skin Intraepithelial T Cells

2010 ◽  
Vol 184 (12) ◽  
pp. 6807-6814 ◽  
Author(s):  
Mingcan Xia ◽  
Qian Qi ◽  
Yan Jin ◽  
David L. Wiest ◽  
Avery August ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tissue Specific ◽  
Specific Localization ◽  
Tcr Signals ◽  
Inducible T Cell Kinase

scholarly journals Epigenetic modification of the human CCR6 gene is associated with stable CCR6 expression in T cells

Blood ◽  
2011 ◽  
Vol 117 (10) ◽  
pp. 2839-2846 ◽  
Author(s):  
Svenja Steinfelder ◽  
Stefan Floess ◽  
Dirk Engelbert ◽  
Barbara Haeringer ◽  
Udo Baron ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Transcriptional Activity ◽  
Epigenetic Modification ◽  
Cell Receptor ◽  
Noncoding Region ◽  
Differentially Methylated Region

Abstract CCR6 is a chemokine receptor expressed on Th17 cells and regulatory T cells that is induced by T-cell priming with certain cytokines, but how its expression and stability are regulated at the molecular level is largely unknown. Here, we identified and characterized a noncoding region of the human CCR6 locus that displayed unmethylated CpG motifs (differentially methylated region [DMR]) selectively in CCR6+ lymphocytes. CCR6 expression on circulating CD4+ T cells was stable on cytokine-induced proliferation but partially down-regulated on T-cell receptor stimulation. However, CCR6 down-regulation was mostly transient, and the DMR within the CCR6 locus remained demethylated. Notably, in vitro induction of CCR6 expression with cytokines in T-cell receptor-activated naive CD4+ T cells was not associated with a demethylated DMR and resulted in unstable CCR6 expression. Conversely, treatment with the DNA methylation inhibitor 5′-azacytidine induced demethylation of the DMR and led to increased and stable CCR6 expression. Finally, when cloned into a reporter gene plasmid, the DMR displayed transcriptional activity in memory T cells that was suppressed by DNA methylation. In summary, we have identified a noncoding region of the human CCR6 gene with methylation-sensitive transcriptional activity in CCR6+ T cells that controls stable CCR6 expression via epigenetic mechanisms.

scholarly journals Thymus epithelium induces tissue-specific tolerance.

1993 ◽  
Vol 177 (4) ◽  
pp. 1153-1164 ◽  
Author(s):  
A Bonomo ◽  
P Matzinger
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Negative Selection ◽  
T Cell Development ◽  
Tissue Specific ◽  
Thymic Epithelium ◽  
Selection Step ◽  
Bone Marrow Derived Cells ◽  
Specific Tolerance

Most current models of T cell development include a positive selection step in the thymus that occurs when T cells interact with thymic epithelium and a negative selection step after encounters with bone marrow-derived cells. We show here that developing T cells are tolerized when they recognize antigens expressed by thymic epithelium, that the tolerance is tissue specific, and that it can occur by deletion of the reactive T cells.

Vβ Spectratype Analysis of Tissue-Infiltrating T Cells Responding to Minor Histocompatibility Antigens Involved in Graft-Versus-Host Disease.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3244-3244
Author(s):  
Jenny Zilberberg ◽  
Gichuru N. Loise ◽  
Thea M. Friedman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Fluorescent Microscopy ◽  
Tunel Staining ◽  
Target Tissue ◽  
Tissue Specific ◽  
Host Disease ◽  
Graft Versus Host

Abstract Lethal graft-versus-host disease (GVHD) can be induced between MHC-matched murine strains expressing multiple minor histocompatibility antigen (miHA) differences. In the C57BL6 (B6)->BALB.B strain combination, both CD4+ and CD8+ donor T cells can mediate severe lethal GVHD, whereas in the B6->CXB-2 model, in which the CXB-2 strain expresses a subset of the BALB.B miHA, only the CD8+ T cells directly potentiate lethality. We have previously used TCR Vβ CDR3-size spectratype analysis to examine the alloreactive B6 CD4+ and CD8+ T cells, isolated from the lymphohematopoietic compartment after transplantation into both BALB.B and CXB-2 recipients. However, since tissue-specific expression of miHA can potentially elicit differential T cell responses, we have extended our T cell repertoire analysis to examine the responses involved in target tissue damage. Infiltrating host-presensitized B6 CD4+ and CD8+ T cells were isolated post-transplant from the intestines, livers and spleens of lethally irradiated (9 Gy; split-dose) BALB.B and CXB-2 recipients. The results indicated some overlapping Vβ CDR3-size skewing in both the CD4+ and CD8+ T cell repertoires between the BALB.B and CXB-2 recipients within the tissues of each recipient strain. Most notably, spectratype analysis demonstrated tissue specific responses unique to each of the BALB.B and CXB-2 infiltrates. In situ observations of the tissue infiltrating alloreactive T cells were performed by fluorescent microscopy of transplanted B6 T cells constitutively expressing eGFP into BALB.B and CXB-2 recipients, in conjunction with immunohistochemical staining of skewed Vβ families. TUNEL staining was also performed to confirm apoptosis of tissue epithelium. These analyses confirmed the increased infiltration of skewed CD4+ and CD8+ Vβ families within the target tissues.

Genetic or Pharmacological Reductions in DNA Methylation Selectively Inhibit Peripheral T-Cell Lymphomagenesis.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2760-2760
Author(s):  
Jennifer J. Trowbridge ◽  
Mingjie Li ◽  
Charles W.M. Roberts ◽  
Stuart H. Orkin
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
T Cell ◽  
Myeloid Leukemia ◽  
Dna Methyltransferase ◽  
Cell Lymphoma ◽  
Dna Demethylation ◽  
T Cell Lymphoma ◽  
Demethylating Agents ◽  
Dna Methylation Inhibitors

Abstract Abstract 2760 The significance of mutations in components of the DNA methylation machinery in blood cancer has become a topic of intense investigation. Unlike genetic modifications, the reversible nature of DNA methylation and other epigenetic changes makes them attractive therapeutic targets. Very recently, mutations in the DNA methyltransferase DNMT3A and the DNA demethylase TET2 were identified in human peripheral T cell lymphoma (PTCL) [1]. These findings provided a novel link between the development and progression of PTCL with deregulation of DNA methylation processes. Importantly, this finding also extended the few known mutations associated with both T-cell lymphoma and myeloid leukemia. Our previous work identified acute sensitivity of MLL-AF9–induced myeloid leukemia (AML) to DNA demethylation through loss or haploinsufficiency of the DNA methyltransferase Dnmt1 [2]. Here, we investigated the sensitivity of PTCL to DNA demethylation. Lymphoma was induced in mice by inactivation of Snf5, a core subunit of the SWI/SNF chromatin remodeling complex, driven by CD4Cre (CD4Cre-Snf52lox). Inactivation of Snf5 leads to rapid onset of mature CD8+ PTCL with a median survival of 10 weeks of age. Strikingly, loss of Dnmt1 in this model (CD4Cre-Snf52lox-Dnmt12lox) completely abrogated development of lymphoma. Furthermore, haploinsufficiency of Dnmt1 was sufficient to increase event-free survival to 13 weeks of age (p=0.0008). Loss or haploinsufficiency of Dnmt1 did not impact normal T cell development in the thymus with the exception of a modest reduction in CD8+ CD44hi memory T cells. Based on the selective response of PTCL to reduced levels of Dnmt1 and DNA methylation, we screened a panel of pharmacological DNA demethylating agents for efficacy in PTCL. We found three putative DNA methylation inhibitors; the nucleoside inhibitor zebularine and non-nucleoside inhibitors RG108 and procainamide, which inhibited proliferation of primary murine PTCL in vitro. These inhibitors were effective at doses that did not restrict the proliferation of normal CD8+ T cells. When these inhibitors were evaluated for efficacy in vivo, both zebularine and procainamide were found to inhibit growth of primary murine PTCL. Together, these results suggest that therapy of PTCL with DNA methylation inhibitors or other DNA demethylating agents may achieve a favorable therapeutic index. Further, these results support the concept of a shared competitive advantage of myeloid leukemia and T-cell lymphoma in carrying mutations in the DNA methylation machinery. [1] Couronne L et al., NEJM, 2012, 366:95-6; [2] Trowbridge et al., Genes Dev, 2012, 26:344-9. Disclosures: No relevant conflicts of interest to declare.

Preliminary Study on the Abnormal DNA Methylation in T Cells from the Patients with Immune Related Pancytopenia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5156-5156
Author(s):  
Zonghong Shao ◽  
Yue Ren ◽  
Rong Fu
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
T Cell ◽  
Mrna Expression ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Mrna Level ◽  
Cd4 T Cell ◽  
Global Dna Methylation ◽  
Normal Controls

Abstract Objective To explore the global DNA methylation and the expression of regulatory genes for methylation in CD4 + T cells of the patients with immune related pancytopenia (IRP) and explore the role of methylation in pathogenesis of IRP. Methods Thirty IRP patients (untreated, n=15; remission, n=15) and 15 healthy donors as controls were enrolled from December 2012 to December 2013. CD4+ T cells were sorted by immunomagnetic separation. The global DNA methylation was tested with enzyme-linked immunosorbent assay (ELISA). The mRNA levels of DNA methylation-related regulating genes, DNA methyltransferases (DNMTs) and methylated CpG binding proteins (MBDs), were measured by real-time quantitative polymerase chain reaction (RT-PCR). Results The level of global DNA methylation in peripheral blood CD4+ T cells of untreated IRP patients (3.525%±2.046%)and remission patients (4.790%±1.471%) were significantly lower than that of normal controls (10.101%±3.449%) respectively (both P<0.05). DNMT3b mRNA level of untreated IRP patients (1.332±0.785) was significantly lower than that of normal controls (2.077±1.059) in CD4+T cells (P<0.05). The mRNA expression of MBD2 was significantly higher in CD4+ T cells from untreated and remission IRP patients (2.999±1.601, 2.055±1.576) than that in controls (0.581±0.247) (both P<0.05). The MBD4 mRNA level was significantly higher in CD4+ T cells from untreated IRP patients (2.736±2.719) compared to that in normal controls (1.167±1.006) (p<0.05). DNMT3b mRNA expression and CD4+ T cell DNA methylation to be positive correlated within IRP patients (r=0.569, p<0.01). The MBD2 mRNA expression negatively correlated with CD4+ T cell DNA methylation and the ratio of Th1/Th2 (r=-0.763, p<0.001; r = -0.652, p<0.05). The global methylation of CD4+ T cells negatively related to the ratio of CD5+ B cells (r= -0.439, p<0.05). Conclusions The globe DNA hypomethylation and abnormal expression of DNA methylation-related enzymes in peripheral blood CD4+ T cells may be related with the pathogenesis of IRP. Disclosures No relevant conflicts of interest to declare.

scholarly journals Tissue-Specific Differences in PD-1 and PD-L1 Expression during Chronic Viral Infection: Implications for CD8 T-Cell Exhaustion

2009 ◽  
Vol 84 (4) ◽  
pp. 2078-2089 ◽  
Author(s):  
Shawn D. Blackburn ◽  
Alison Crawford ◽  
Haina Shin ◽  
Antonio Polley ◽  
Gordon J. Freeman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
Therapeutic Interventions ◽  
Chronic Viral Infection ◽  
Anatomical Location ◽  
T Cell Exhaustion ◽  
Tissue Specific ◽  
Cell Exhaustion

ABSTRACT The PD-1/PD-L pathway plays a major role in regulating T-cell exhaustion during chronic viral infections in animal models, as well as in humans, and blockade of this pathway can revive exhausted CD8+ T cells. We examined the expression of PD-1 and its ligands, PD-L1 and PD-L2, in multiple tissues during the course of chronic viral infection and determined how the amount of PD-1 expressed, as well as the anatomical location, influenced the function of exhausted CD8 T cells. The amount of PD-1 on exhausted CD8 T cells from different anatomical locations did not always correlate with infectious virus but did reflect viral antigen in some tissues. Moreover, lower expression of PD-L1 in some locations, such as the bone marrow, favored the survival of PD-1Hi exhausted CD8 T cells, suggesting that some anatomical sites might provide a survival niche for subpopulations of exhausted CD8 T cells. Tissue-specific differences in the function of exhausted CD8 T cells were also observed. However, while cytokine production did not strictly correlate with the amount of PD-1 expressed by exhausted CD8 T cells from different tissues, the ability to degranulate and kill were tightly linked to PD-1 expression regardless of the anatomical location. These observations have implications for human chronic infections and for therapeutic interventions based on blockade of the PD-1 pathway.

scholarly journals Hypomethylation of STAT1 and HLA-DRB1 is associated with type-I interferon-dependent HLA-DRB1 expression in lupus CD8+ T cells

2018 ◽  
Author(s):  
Shaylynn Miller ◽  
Patrick Coit ◽  
Elizabeth Gensterblum-Miller ◽  
Paul Renauer ◽  
Nathan C Kilian ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Mrna Levels ◽  
Healthy Controls ◽  
Genome Wide

AbstractObjectiveWe examined genome-wide DNA methylation changes in CD8+ T cells from lupus patients and controls, and investigated the functional relevance of some of these changes in lupus.MethodsGenome-wide DNA methylation of lupus and age, sex, and ethnicity-matched control CD8+ T cells was measured using the Infinium MethylationEPIC arrays. Measurement of relevant cell subsets was performed via flow cytometry. Gene expression was quantified by qPCR.ResultsLupus CD8+ T cells had 188 hypomethylated CpG sites compared to healthy matched controls. Among the most hypomethylated were sites associated with HLA-DRB1. Genes involved in the type-I interferon response, including STAT1, were also found to be hypomethylated. IFNα upregulated HLA-DRB1 expression on lupus but not control CD8+ T cells. Lupus and control CD8+ T cells significantly increased STAT1 mRNA levels after treatment with IFNα. The expression of CIITA, a key interferon/STAT1 dependent MHC-class II regulator, is induced by IFNα in lupus CD8+ T cells, but not healthy controls. Co-incubation of naïve CD4+ T cells with IFNα-treated CD8+ T cells led to CD4+ T cell activation, determined by increased expression of CD69, in lupus patients but not in healthy controls. This can be blocked by neutralizing antibodies targeting HLA-DR.ConclusionsLupus CD8+ T cells are epigenetically primed to respond to type-I interferon. We describe an HLA-DRB1+ CD8+ T cell subset that can be induced by IFNα in lupus patients. A possible pathogenic role for CD8+ T cells in lupus that is dependent upon a high type-I interferon environment and epigenetic priming warrants further characterization.

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