scholarly journals The Functional DNA Methylation Signatures Relevant to Altered Immune Response of Neonatal T Cells with l-Arginine Supplementation

Nutrients ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 2780
Author(s):  
Hong-Ren Yu ◽  
Te-Yao Hsu ◽  
Ching-Chang Tsai ◽  
Hsin-Chun Huang ◽  
Hsin-Hsin Cheng ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
Cord Blood ◽  
Immune Function ◽  
Cd4 T Cells ◽  
Biological Activities ◽  
P Value ◽  
Cpg Dinucleotides ◽  
Functional Dna ◽  
Arginine Supplementation

l-Arginine is an important nutrient in the infant diet that significantly regulates the maturation of the immune system in neonates, including the maturation of CD4+ T cells. The biological activities of CD4+ T cells differ substantially between neonates and adults, and these differences may be governed by epigenetic processes. Investigating these differences and the causative processes may help understand neonatal and developmental immunity. In this study, we compared the functional DNA methylation profiles in CD4+ T cells of neonates and adults, focusing on the role of l-arginine supplementation. Umbilical cord blood and adult CD4+ T cells were cultured with/without l-arginine treatment. By comparing DNA methylation in samples without l-arginine treatment, we found that CD4+ T cells of neonatal cord blood generally showed higher DNA methylation than those of adults (average CpG methylation percentage 0.6305 for neonate and 0.6254 for adult, t-test p-value < 0.0001), suggesting gene silencing in neonates. By examining DNA methylation patterns of CpG dinucleotides induced by l-arginine treatment, we found that more CpG dinucleotides were hypomethylated and more genes appeared to be activated in neonatal T-cells as compared with adult. Genes activated by l-arginine stimulation of cord blood samples were more enriched regarding immune-related pathways. CpG dinucleotides at IL-13 promoter regions were hypomethylated after l-arginine stimulation. Hypomethylated CpG dinucleotides corresponded to higher IL-13 gene expression and cytokine production. Thus, DNA methylation partially accounts for the mechanism underlying differential immune function in neonates. Modulatory effects of l-arginine on DNA methylation are gene-specific. Nutritional intervention is a potential strategy to modulate immune function of neonates.

Plasmacytoid CD123+ Dendritic Cell Recovery Is An Independent Predictor of Survival after Unrelated Cord Blood Transplant (UCBT).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2228-2228
Author(s):  
Davi d A Wilfret ◽  
Adam Mendizabal ◽  
Mel Reese ◽  
Richard Vinesett ◽  
Joanne Kurtzberg ◽  
...  
Keyword(s):  
T Cells ◽  
Cord Blood ◽  
Survival Probability ◽  
Cd4 T Cells ◽  
Independent Predictor ◽  
Absolute Number ◽  
Time Dependent ◽  
Cd4 T Cell ◽  
P Value ◽  
Cord Blood Transplant

Abstract BACKGROUND: Reconstitution of adaptive immunity is critical for long term survival following hematopoietic cell transplantation. Antigen presenting dendritic cells (DC) and CD4+ T cells are critical for attaining immunity. Unrelated umbilical cord blood transplantation (UCBT) is a suitable option for those who lack HLA-matched sibling donors. However, opportunistic infections remain the major cause of non-relapse mortality. Analysis of the COBLT trial reported that successful recovery of antiviral immunity is associated with a reduced rate of relapse (BBMT. 2006;12:1335). METHODS: Between July, 2005 and December, 2007, 95 children with successful donor cell engraftment were assessed for reconstitution of DC subsets along with CD4+ T cells to analyze their impact on overall survival (OS) following myeloablative conditioning and a single cord blood transplant at Duke University. Utilizing Trucount™ methodology 4-color surface FACS was employed to enumerate absolute cell numbers at 3, 6, 12, 24, 36 months after transplant. RESULTS: 52 (55%) of patients were transplanted for non-malignant diseases while 43 (45%) had malignancies. The median age was 2.7 years (range, 0.1–18.0). 55 (59%) of patients were male and 74 (78%) were white. 38 (40%) were 4/6 HLA match, 39 (41%) were 5/6 and 18 (19%) were 6/6. The median infused TNC was 7.2 x 107/kg (range, 0.8–31.6), median infused CD34+ was 1.9 x 105/kg (range, 0.0–11.0), and median infused CD3+ T cells was 11.7 x 106/kg (range, 0.0–90.3). Of the 95 patients considered in this analysis, 6 patients died before day 180 with a day 180 survival probability of 93.7% (95% CI 86.5%–97.1%), 11 patients died between day 180 and 365 with a 1-year survival probability of 81.7% (95% CI 72.2%–88.2%) and 8 patients died between day 365 and 730 with a 2-year survival probability of 69.1% (95% CI 57.1%–78.3%). In an univariate analysis of OS post-transplant, HLA match of 5/6 or 6/6 (HR=0.41, p=0.02), absolute number of CD123+ “plasmacytoid” dendritic cells (pDC) &gt;8 cells/ul and a non-malignant diagnosis (HR=0.25, p=0.001) were associated with a decreased risk of death, while CD4+ T cell and CD11c+ “myeloid” DC recovery had no statistical impact, Table 1. In this cohort, where all studied patients have successfully engrafted with relatively high cell dose; gender, race, CMV serology, TNC, CD34+ cell dose, TBI had no discernible impact. There were two prognostic factors that maintained statistical significance in a multivariate model; Absolute number of CD123+ DC &gt;8 cells/ul (HR=0.44, p=0.05) and non-malignant disease (HR=0.27, p=0.002), while HLA was not statistically significant (HR=0.53, p=0.10), Table I. Importantly, non-malignant patients do not get TBI, do not die due to relapse, tend to be younger and such receive higher cell doses. CONCLUSION: This is the first analysis to our knowledge to suggests that the absolute number of CD123+ pDC &gt;8 Cells/ul is an independent predictor of survival after UCBT. These cells are the most potent APC providing interferon-alpha mediated activation of the immune system besides presentation of antigenic peptides. There is a need for better understanding of the factors that may impact pDC reconstitution so novel therapeutic approaches may improve survival after UCBT. Univariate Modeling of OS HR (95% CI) p-value Interpretation Gender Female 1.52 (0.72–3.21) 0.27 NS Male 1.00 Disease Non-Malignant 0.25 (0.11–0.58) 0.001 Non-Malignant patients have a 75% decreased risk of dieing as compared to malignant Malignant 1.00 TNC/kg 1.03 (0.97–1.10) 0.35 NS CD34+/kg 1.01 (0.86–1.19) 0.87 NS CD3+/kg 1.01 (0.98–1.04) 0.68 NS HLA Match 5/6 or 6/6 0.41 (0.20–0.88) 0.02 59% decreased risk of dieing with a HLA match of 5/6 or 6/6 4/6 1.00 41% decreased risk Abs CD4+ T cells Time-dependent 0.59 (0.23–1.52) 0.28 of dieing if you get 200 abs CD4+ T-cell Absolute Number of CD123+ DC (pDC/ul) Time-Dependent 0.42 (0.18–0.95) 0.04 58% decreased risk of dieing if you get &gt;8 Absolute Number of CD11c+ (Myeloid DC/ul) Time-dependent ( 1.05 (0.44–2.47) 0.92 NS CD4+ (%CD4+) Time-dependent 2.12 (0.80–5.62) 0.13 NS Multivariate Model HR (95% CI) p-value Interpretation HLA Match 5/6 or 6/6 0.53 (0.25–1.14) 0.10 47% decreased risk of dieing with a HLA match of 5/6 or 6/6 4/6 1.00 Absolute Number of CD123+ (Plasmacytoid DC/ul) Time-Dependent 0.44 (0.20–1.00) 0.05 56% decreased risk of dieing if you get &gt;8/ul Disease Non-Malignant 0.27 (0.12–0.63) 0.002 Non-Malignant patients have a 75% decreased risk of dieing as compared to malignant Malignant 1.00

scholarly journals Immune classification of clear cell renal cell carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sumeyye Su ◽  
Shaya Akbarinejad ◽  
Leili Shahriyari
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Renal Cell ◽  
Cd4 T Cells ◽  
Immune Cell ◽  
Clear Cell ◽  
P Value ◽  
Cell Type ◽  
Primary Tumors ◽  
Immune Cell Type

AbstractSince the outcome of treatments, particularly immunotherapeutic interventions, depends on the tumor immune micro-environment (TIM), several experimental and computational tools such as flow cytometry, immunohistochemistry, and digital cytometry have been developed and utilized to classify TIM variations. In this project, we identify immune pattern of clear cell renal cell carcinomas (ccRCC) by estimating the percentage of each immune cell type in 526 renal tumors using the new powerful technique of digital cytometry. The results, which are in agreement with the results of a large-scale mass cytometry analysis, show that the most frequent immune cell types in ccRCC tumors are CD8+ T-cells, macrophages, and CD4+ T-cells. Saliently, unsupervised clustering of ccRCC primary tumors based on their relative number of immune cells indicates the existence of four distinct groups of ccRCC tumors. Tumors in the first group consist of approximately the same numbers of macrophages and CD8+ T-cells and and a slightly smaller number of CD4+ T cells than CD8+ T cells, while tumors in the second group have a significantly high number of macrophages compared to any other immune cell type (P-value $$<0.01$$ < 0.01 ). The third group of ccRCC tumors have a significantly higher number of CD8+ T-cells than any other immune cell type (P-value $$<0.01$$ < 0.01 ), while tumors in the group 4 have approximately the same numbers of macrophages and CD4+ T-cells and a significantly smaller number of CD8+ T-cells than CD4+ T-cells (P-value $$<0.01$$ < 0.01 ). Moreover, there is a high positive correlation between the expression levels of IFNG and PDCD1 and the percentage of CD8+ T-cells, and higher stage and grade of tumors have a substantially higher percentage of CD8+ T-cells. Furthermore, the primary tumors of patients, who are tumor free at the last time of follow up, have a significantly higher percentage of mast cells (P-value $$<0.01$$ < 0.01 ) compared to the patients with tumors for all groups of tumors except group 3.

scholarly journals Trichloroethylene-induced alterations in DNA methylation were enriched in polycomb protein binding sites in effector/memory CD4+ T cells

2017 ◽  
Vol 3 (3) ◽  
Author(s):  
Kathleen M. Gilbert ◽  
Sarah J. Blossom ◽  
Brad Reisfeld ◽  
Stephen W. Erickson ◽  
Kanan Vyas ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
Protein Binding ◽  
Binding Sites ◽  
Cd4 T Cells ◽  
Effector Memory ◽  
Protein Binding Sites ◽  
Polycomb Protein ◽  
Memory Cd4 T Cells

scholarly journals Differentiation and stability of T helper 1 and 2 cells derived from naive human neonatal CD4+ T cells, analyzed at the single-cell level.

1996 ◽  
Vol 184 (2) ◽  
pp. 473-483 ◽  
Author(s):  
T Sornasse ◽  
P V Larenas ◽  
K A Davis ◽  
J E de Vries ◽  
H Yssel
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Cd4 T Cells ◽  
Biological Activities ◽  
Th2 Cells ◽  
Cell Phenotype ◽  
T Helper ◽  
Th1 Cell ◽  
Th2 Cell ◽  
Th1 And Th2

The development of CD4+ T helper (Th) type 1 and 2 cells is essential for the eradication of pathogens, but can also be responsible for various pathological disorders. Therefore, modulation of Th cell differentiation may have clinical utility in the treatment of human disease. Here, we show that interleukin (IL) 12 and IL-4 directly induce human neonatal CD4- T cells, activated via CD3 and CD28, to differentiate into Th1 and Th2 subsets. In contrast, IL-13, which shares many biological activities with IL-4, failed to induce T cell differentiation, consistent with the observation that human T cells do not express IL-13 receptors. Both the IL-12-induced Th1 subset and the IL-4-induced Th2 subset produce large quantities of IL-10, confirming that human IL-10 is not a typical human Th2 cytokine. Interestingly, IL-4-driven Th2 cell differentiation was completely prevented by an IL-4 mutant protein (IL-4.Y124D), indicating that this molecule acts as a strong IL-4 receptor antagonist. Analysis of single T cells producing interferon gamma or IL-4 revealed that induction of Th1 cell differentiation occurred rapidly and required only 4 d of priming of the neonatal CD4+ T cells in the presence of IL-12. The IL-12-induced Th1 cell phenotype was stable and was not significantly affected when repeatedly stimulated in the presence of recombinant IL-4. In contrast, the differentiation of Th2 cells occurred slowly and required not only 6 d of priming, but also additional restimulation of the primed CD4+ T cells in the presence of IL-4. Moreover, IL-4-induced Th2 cell phenotypes were not stable and could rapidly be reverted into a population predominantly containing Th0 and Th1 cells, after a single restimulation in the presence of IL-12. The observed differences in stability of IL-12- and IL-4-induced human Th1 and Th2 subsets, respectively, may have implications for cytokine-based therapies of chronic disease.

scholarly journals Cell intrinsic characteristics of human cord blood naïve CD4 T cells

2018 ◽  
Vol 193 ◽  
pp. 51-57 ◽  
Author(s):  
Ramiah D. Jacks ◽  
Taylor J. Keller ◽  
Alexander Nelson ◽  
Michael I. Nishimura ◽  
Paula White ◽  
...  
Keyword(s):  
T Cells ◽  
Cord Blood ◽  
Cd4 T Cells ◽  
Human Cord Blood

scholarly journals Epigenetic inheritance of DNA methylation limits activation-induced expression of FOXP3 in conventional human CD25-CD4+ T cells

2008 ◽  
Vol 20 (8) ◽  
pp. 1041-1055 ◽  
Author(s):  
M. Nagar ◽  
H. Vernitsky ◽  
Y. Cohen ◽  
D. Dominissini ◽  
Y. Berkun ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
Cd4 T Cells ◽  
Epigenetic Inheritance ◽  
Induced Expression

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.

The Significance of mTOR Inhibitor, Everolimus in TGF-β-Induced Regulatory T cells from Cord Blood

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2180-2180
Author(s):  
Tokiko Nagamura-Inoue ◽  
Seiichiro Kobayashi ◽  
Kazuo Ogami ◽  
Yuki Yamamoto ◽  
Kiyoko Izawa ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cord Blood ◽  
Cell Population ◽  
Cd4 T Cells ◽  
Mtor Inhibitor ◽  
Ex Vivo ◽  
Mtor Inhibitors ◽  
Ex Vivo Expansion ◽  
The Impact

Abstract Abstract 2180 Background: Regulatory T cells (Tregs) play an important role in immune-tolerance to allograft. Cord blood (CB) is rich in naïve T cells and is a promising source of inducible Tregs (iTregs), since it was reported that stable iTregs may be derived exclusively from naïve T cells. However, the standard method for iTregs has not yet been established. Here we studied the impact of mTOR inhibitors, rapamycin (Rap) and everolimus (Eve), on ex vivo expansion of iTregs from CB-CD4+ T cells. Methods: CB-CD4+ T cell were isolated using anti-CD4 monoclonal antibody (MAb)-conjugated magnetic beads, and cultured in a flask coated with anti-CD3/CD28 MAbs and supplemented with IL-2 and TGF-β in the presence or absence of Rap or Eve. After two weeks of culture, the total number of CD4+ T cells was calculated, and the incidence of CD25+Foxp3+ cell population among those was estimated by FACS. Results and Discussions: Both Rap and Eve significantly increased the incidence of CD25+Foxp3+ cell population in CD4+ T cells. However, Rap apparently inhibited their growth and did not increase the absolute number of CD25+Foxp3+ cells in comparison to the control. On the other hand, Eve contributed to efficient expansion of iTregs at the concentration between 1 and 50ng/ml without no significant inhibition of their growth. Expansion of CD4+ T cells with TGF-β and Eve yielded 71.5 ±23.5% purity of CD25+Foxp3+ cells which also expressed CTLA-4 as well as the memory phenotype, while the purity obtained with TGF-β only was 47.4±30.0% and that without TGF-β/Eve was 7.3±4.5%. Thus, an average of 2.95±2.8 x107 iTregs were obtained from the initial input of 5×104 CD4+ T cells. The resulting iTregs with TGF-β, TGF-β/Rap and TGF-β/Eve inhibited the proliferation of CFSE-labeled T cells stimulated with allogeneic dendritic cells. The precise mechanism for Foxp3 induction by mTOR inhibitors still remains to be elucidated. Furthermore, we found that expression of CD26 (DPP-IV) was significantly down-regulated in CD4+ T cells expanded with TGF-β and profoundly with TGF-β/Eve, while CD127 was negative after culture in all the conditions. Mean fluorescence intensity of CD26 indicated 67.5 in CD4+ T cells without TGF-β, 1.58 with TGF-β, 0.18 with TGF-β/Rap and 0.12 with TGF-β/Eve, respectively. Accordingly, CD26 negativity may be an indicator of iTregs together with Foxp3. Conclusion: mTOR inhibitor, Eve, is an efficient co-inducer of iTregs and applicable to ex vivo expansion of iTregs in a clinical setting. Disclosures: No relevant conflicts of interest to declare.

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