In vivo fluctuation of Tax, Foxp3, CTLA-4, and GITR mRNA expression in CD4+CD25+ T cells of patients with human T-lymphotropic virus type 1-associated myelopathy

Ramı́rez, Eugenio; Cartier, Luis; Rodriguez, L.; Alberti, Carolina; Ma, Valenzuela

doi:10.1590/s0100-879x2010007500107

Cited by 17 publications

(38 citation statements)

References 33 publications

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“…Therefore, we analyzed the phenotype of the increased FoxP3 + cells and observed that CTLA-4 and GITR expression of FoxP3 + T cells in HAM/TSP patient was significantly reduced compared to uninfected individuals (Figure 5C). A similar observation was reported previously that the expression level of FoxP3, GITR, or CTLA-4 mRNA in CD4 + CD25 + T cells of HAM/TSP patients is lower than that of HD [44]. That report used CD4 + CD25 + as a marker of T reg cells, but CD4 + CD25 + T cells contain not only FoxP3 + T reg cells but also FoxP3 − activated T cells.…”

Section: Discussionsupporting

confidence: 83%

HTLV-1 modulates the frequency and phenotype of FoxP3+CD4+T cells in virus-infected individuals

et al. 2012

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Background HTLV-1 utilizes CD4 T cells as the main host cell and maintains the proviral load via clonal proliferation of infected CD4 + T cells. Infection of CD4 + T cells by HTLV-1 is therefore thought to play a pivotal role in HTLV-1-related pathogenicity, including leukemia/lymphoma of CD4 + T cells and chronic inflammatory diseases. Recently, it has been reported that a proportion of HTLV-1 infected CD4 + T cells express FoxP3, a master molecule of regulatory T cells. However, crucial questions remain unanswered on the relationship between HTLV-1 infection and FoxP3 expression. Results To investigate the effect of HTLV-1 infection on CD4 + T-cell subsets, we used flow cytometry to analyze the T-cell phenotype and HTLV-1 infection in peripheral mononuclear cells (PBMCs) of four groups of subjects, including 23 HTLV-1-infected asymptomatic carriers (AC), 10 patients with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), 10 patients with adult T-cell leukemia (ATL), and 10 healthy donors. The frequency of FoxP3 + cells in CD4 + T cells in AC with high proviral load and patients with HAM/TSP or ATL was higher than that in uninfected individuals. The proviral load was positively correlated with the percentage of CD4 + T cells that were FoxP3 + . The CD4 + FoxP3 + T cells, themselves, were frequently infected with HTLV-1. We conclude that FoxP3 + T- cells are disproportionately infected with HTLV-1 during chronic infection. We next focused on PBMCs of HAM/TSP patients. The expression levels of the T reg associated molecules CTLA-4 and GITR were decreased in CD4 + FoxP3 + T cells. Further we characterized FoxP3 + CD4 + T-cell subsets by staining CD45RA and FoxP3, which revealed an increase in CD45RA − FoxP3 low non-suppressive T-cells. These findings can reconcile the inflammatory phenotype of HAM/TSP with the observed increase in frequency of FoxP3 + cells. Finally, we analyzed ATL cells and observed not only a high frequency of FoxP3 expression but also wide variation in FoxP3 expression level among individual cases. Conclusions HTLV-1 infection induces an abnormal frequency and phenotype of FoxP3 + CD4 + T cells.

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Section: Discussionsupporting

confidence: 83%

HTLV-1 modulates the frequency and phenotype of FoxP3+CD4+T cells in virus-infected individuals

et al. 2012

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“…Notably, only the top 1-2% of these cells (CD4 + CD25 hi ) is considered to be functionally suppressive (13), and this frequency varies physiologically, especially with increased age (14). Several additional markers used to characterize Tregs in healthy donors, including GITR, CD127, and CTLA4, are unreliable here due to their alteration by HTLV-1 related activation (15, 16). …”

Section: Introductionmentioning

confidence: 99%

Epigenetic Modification of the FoxP3 TSDR in HAM/TSP Decreases the Functional Suppression of Tregs

Anderson

Enose-Akahata

Massoud

et al. 2014

J Neuroimmune Pharmacol

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HTLV-1 is a human retrovirus that is associated with the neuroinflammatory disorder HTLV-1 associated myelopathy/ tropical spastic paraparesis (HAM/TSP). In these patients, HTLV-1 is primarily found in the CD4+CD25+ T cell subset (Regulatory T cells:Tregs), which is responsible for peripheral immune tolerance and is known to be dysfunctional in HAM/TSP. Recent evidence suggests that FoxP3 expression and function is determined epigenetically through DNA demethylation in the Treg-specific demethylated region (TSDR). We analyzed the methylation of the TSDR in PBMCs, CD4+ T cells, and CD4+CD25+ T cells from normal healthy donors (NDs) and HAM/TSP patients. We demonstrated that there is decreased demethylation in analyzed PBMCs and CD4+CD25+ T cells from HAM/TSP patients as compared to NDs. Furthermore, decreased TSDR demethylation was associated with decreased functional suppression by Tregs. Additionally, increased HTLV-1 Tax expression in HAM/TSP PBMC culture correlated with a concomitant decline in FoxP3 TSDR demethylation. Overall, we suggest that HTLV-1 infection decreases Treg functional suppressive capacity in HAM/TSP through modification of FoxP3 TSDR demethylation and that dysregulated Treg function may contribute to HAM/TSP disease pathogenesis.

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“…CD25+ cells were enriched with PE‐anti‐CD25 and anti‐PE magnetic beads (Miltenyi Biotec, Bergisch Gladbach, Germany) using the Midi‐MACS system (Miltenyi Biotech). The purity of the resulting CD4+CD25+ T cells was shown to be 90% by flow cytometry [Ramirez et al, ].…”

Section: Methodsmentioning

confidence: 99%

Tax secretion from peripheral blood mononuclear cells and tax detection in plasma of patients with human T‐lymphotropic virus‐type 1‐associated myelopathy/tropical spastic paraparesis and asymptomatic carriers

Medina

Quintremil

Alberti

et al. 2015

Journal of Medical Virology

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Human T-lymphotropic virus-type 1 (HTLV-1) is the etiologic agent of the neurologic disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Tax viral protein plays a critical role in viral pathogenesis. Previous studies suggested that extracellular Tax might involve cytokine-like extracellular effects. We evaluated Tax secretion in 18 h-ex vivo peripheral blood mononuclear cells (PBMCs) cultures from 15 HAM/TSP patients and 15 asymptomatic carriers. Futhermore, Tax plasma level was evaluated from other 12 HAM/TSP patients and 10 asymptomatic carriers. Proviral load and mRNA encoding Tax were quantified by PCR and real-time RT-PCR, respectively. Intracellular Tax in CD4(+)CD25(+) cells occurred in 100% and 86.7% of HAM/TSP patients and asymptomatic carriers, respectively. Percentage of CD4(+)CD25(+) Tax+, proviral load and mRNA encoding Tax were significantly higher in HAM/TSP patients. Western blot analyses showed higher secretion levels of ubiquitinated Tax in HAM/TSP patients than in asymptomatic carriers. In HTLV-1-infected subjects, Western blot of plasma Tax showed higher levels in HAM/TSP patients than in asymptomatic carriers, whereas no Tax was found in non-infected subjects. Immunoprecipitated plasma Tax resolved on SDS-PAGE gave two major bands of 57 and 48 kDa allowing identification of Tax and Ubiquitin peptides by mass spectrometry. Relative percentage of either CD4(+)CD25(+) Tax+ cells, or Tax protein released from PBMCs, or plasma Tax, correlates neither with tax mRNA nor with proviral load. This fact could be explained by a complex regulation of Tax expression. Tax secreted from PBMCs or present in plasma could potentially become a biomarker to distinguish between HAM/TSP patients and asymptomatic carriers.

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In vivo fluctuation of Tax, Foxp3, CTLA-4, and GITR mRNA expression in CD4+CD25+ T cells of patients with human T-lymphotropic virus type 1-associated myelopathy

Cited by 17 publications

References 33 publications

HTLV-1 modulates the frequency and phenotype of FoxP3+CD4+T cells in virus-infected individuals

HTLV-1 modulates the frequency and phenotype of FoxP3+CD4+T cells in virus-infected individuals

Epigenetic Modification of the FoxP3 TSDR in HAM/TSP Decreases the Functional Suppression of Tregs

Tax secretion from peripheral blood mononuclear cells and tax detection in plasma of patients with human T‐lymphotropic virus‐type 1‐associated myelopathy/tropical spastic paraparesis and asymptomatic carriers

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