scholarly journals Sex Hormones and Gender Influence the Expression of Markers of Regulatory T Cells in SLE Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Ram P. Singh ◽  
David S. Bischoff
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Sex Hormones ◽  
Fold Increase ◽  
Foxp3 Expression ◽  
Plasma Testosterone ◽  
Cell Phenotype ◽  
Foxp3 Mrna ◽  
Healthy Females ◽  
Healthy Males

Regulatory T cells have been implicated in the regulation and maintenance of immune homeostasis. Whether gender and sex hormones differentially influence the expression and function of regulatory T cell phenotype and their influence on FoxP3 expression remains obscure. We provide evidence in this study that the number and percent of human regulatory T cells (Tregs) expressing CD4+ and CD8+ are significantly reduced in healthy females compared to healthy males. In addition, both CD4+CD25+hi and CD8+CD25+hi subsets in healthy males have a 2-3 fold increase in FoxP3 mRNA expression compared to healthy females. Female SLE patients, compared to healthy women, have elevated plasma levels of estradiol and decreased levels of testosterone. Higher levels of testosterone correlate with higher expression of FoxP3 in CD4+CD25hiCD127low putative Tregs in women with SLE. Incubation of CD4+ regulatory T cells with 17β-estradiol at physiological levels generally decreased FoxP3 expression in females with SLE. These data suggest that females may be more susceptible than males to SLE and other autoimmune diseases in part because they have fewer Tregs and reduced FoxP3 expression within those cells due to normal E2 levels which suppress FoxP3 expression. In addition, low levels of plasma testosterone in women may further reduce the ability of the Tregs to express FoxP3. These data suggest that gender and sex hormones can influence susceptibility to SLE via effects on regulatory T cells and FoxP3 expression.

IL-2 Therapy Promotes the Expansion of Human CD4+CD25+ Regulatory T Cells and Selectively Upregulates the Expression of FOXP3 in T Cells In Vivo.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1257-1257
Author(s):  
Emmanuel Zorn ◽  
Erik A. Nelson ◽  
Mehrdad Mohseni ◽  
Despina Litsa ◽  
Haesook Kim ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Regulatory T Cells ◽  
Nk Cells ◽  
Quantitative Pcr ◽  
Peripheral Blood ◽  
Fold Increase ◽  
Foxp3 Expression ◽  
Prolonged Administration

Abstract Recombinant IL-2 has been used extensively in clinical trials to enhance a wide range of immune responses. Overall this strategy has had limited efficacy. Recent evidence suggests that IL-2 plays a key role in the generation and maintenance of CD4+CD25+ regulatory T cells (Treg) in vivo. In our study, we investigated the effect of prolonged administration of recombinant IL-2 on Treg in vivo. In a retrospective analysis, we first examined CD4+CD25+ Treg in blood samples collected from 21 cancer patients before and after they started continuous treatment with IL-2 at a dose of 2 X 105 U/m2/day for 3 months. Nine patients received IL-2 beginning 3 months after CD6 T cell depleted allogeneic bone marrow transplantation (BMT) for CML. The remaining 12 patients received IL-2 as treatment for advanced solid tumors. Overall toxicity was minimal and none of the transplant patients developed GVHD following IL-2 administration. Previous reports demonstrated that this prolonged treatment with low-dose IL-2 resulted in the expansion of CD56+CD3− NK cells in peripheral blood. Further analysis showed that 15 patients exhibited an expansion of Treg in peripheral blood 26 to 77 days after beginning IL-2 as demonstrated by an increase in the CD4+CD25+/CD3+ ratio (median fold increase 2.68; range 1.3 to 59). Three patients had no significant change and 3 patients demonstrated a decreased Treg/CD3 ratio. Using RNA from the same samples we also measured the expression of the Treg specific transcription factor FOXP3 by quantitative PCR. Nineteen of 21 patients showed a marked increase in FOXP3 expression following IL-2 treatment (8.38 median fold increase; range 1.4 to 41.5). Only 2 of 21 patients had lower FOXP3 expression after IL-2 administration. Since IL-2 treatment resulted in the expansion of NK cells as well as Treg, we purified CD56+CD3− NK cells and CD4+ T cells from patient samples collected post-IL-2 treatment, and measured FOXP3 gene expression in both subsets. In 4 analyzed cases, FOXP3 was selectively expressed in CD4+ T cells. Further analysis of purified Treg and NK cells incubated with IL-2 in vitro confirmed that FOXP3 expression was selectively induced in Treg, and also suggested that the in vivo increase in FOXP3 expression resulted from both Treg expansion and up-regulation of gene expression at the single cell level. To study the duration of the IL-2 effect, we analyzed additional samples collected 2 to 8 months after IL-2 treatment was completed. Nine of 10 patient samples tested showed a decrease in the CD4+CD25+/CD3+ ratio (1.39 median fold decrease; range 1.13 to 15.02). Using quantitative PCR, expression of FOXP3 decreased for 6 of 8 patients tested (10.76 median fold decrease; range 1.22 to 88.31). These results indicate that prolonged administration of IL-2 promotes the expansion of CD4+CD25+ Treg in vivo and also has a direct effect on FOXP3 expression. Although administration of IL-2 has previously been used to enhance T and NK cell responses, this study demonstrates that IL-2 therapy predominantly reinforces the regulatory component of the immune response, and may provide a means for controlling immune reactions in vivo.

The Decrease of Regulatory T Cells through the Low Levels of FOXP3 Expression Mediated by NFAT1 in Infancy with Autoimmune Neutropenia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 666-666
Author(s):  
Kazuhiro Nakamura ◽  
Mizuka Miki ◽  
Syuhei Karakawa ◽  
Rie Onodera ◽  
Emi Kurita ◽  
...  
Keyword(s):  
T Cells ◽  
Autoimmune Disease ◽  
Regulatory T Cells ◽  
Age Groups ◽  
Foxp3 Expression ◽  
Autoimmune Neutropenia ◽  
Foxp3 Mrna ◽  
Healthy Infants ◽  
Standard Value ◽  
Infancy And Early Childhood

Abstract CD4+ /CD25+ regulatory T cells have been recognized to regulate the maintenance of self-tolerance, and several human autoimmune diseases in adulthood. To date, little is known about the standard value of regulatory T cells in infancy and childhood and about its involvement in pediatric autoimmune disease. Autoimmune neutropenia (AIN) in infancy is a common disorder characterized by chronic neutropenia, the detection of antineutrophil antibodies in sera, and spontaneous resolution of neutropenia within several months to a few years. In this study we examined the frequencies of regulatory T cells in various normal age groups and AIN patients to elucidate the involvement of regulatory T cells in AIN known as a representative autoimmune disease in infancy and early childhood. Blood samples from healthy neonates (n = 22), infants (1 month through 3 years in age, n = 21), adults (n = 12) and AIN patients (1 month through 3 years in age, n = 22) were obtained after informed consent. The frequencies of regulatory T cells were assessed by the expression of CD4, CD25, and FOXP3 using flow cytometry. The mRNA expressions of FOXP3 and its transcription factor, NFAT in CD4+ /CD25+ regulatory T cells were determined by quantitative real-time PCR. The frequency of CD4+ /CD25high regulatory T cells known as pure regulatory T cells fraction was highest in neonates and decreased by aging. Notably, the number of CD4+ /CD25high regulatory T cells in AIN patients significantly decreased, compared with that of age-matched healthy infants (P < 0.01) and the ratio of intracytosolic FOXP3 expression of each regulatory T cell fraction in AIN patients was lower than that of age-matched healthy infants (P < 0.05). Next, we purified CD4+ /CD25+ T cells by using FACS-Aria (more than 95% of purity) and the mRNA expressions in CD4+ /CD25+ T cells were quantified. The expressions of FOXP3 and NFAT1 mRNA in AIN patients were significantly lower than those of healthy infants (P < 0.05). The low level of FOXP3 mRNA in patients well correlated with the expression level of NFAT1 mRNA, implying that the expression of FOXP3 was mediated by NFAT1. Furthermore, the decreased frequency of CD4+ /CD25high regulatory T cells and FOXP3-positive cells in AIN patients were restored to normal levels when the neutrophil count was spontaneously recovered. These results strongly suggest that regulatory T cells play an important role in the immunopathophysiology of AIN in childhood.

Identification of a Human Natural Regulatory T Cell Micro-RNA Signature and Demonstration of the Major Role Played by miR31 in the Control of Foxp3 Expression

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1526-1526
Author(s):  
Redouane Rouas ◽  
Hussein Fayyad Kazan ◽  
Nabil El Zein ◽  
Philippe Lewalle ◽  
Françoise Rothé ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Foxp3 Expression ◽  
Micro Rna ◽  
Global Level ◽  
Foxp3 Mrna ◽  
Protein Levels ◽  
Micro Rnas ◽  
Considerable Debate ◽  
The Moment

Abstract Regulatory T cells are the main mediators of dominant tolerance. Their mechanisms of action and applications are subjects of considerable debate at the moment. However, a micro-RNA human Treg signature has not been described yet. We investigated human natural regulatory T-cells derived from cord blood and identified, using TLDA and qPCR, a signature composed of five micro-RNAs (21, 31, 125a, 181c and 374). Among those five, two were considerably under-expressed (miR31 and miR125a). We identified a functional binding site for miR31 in the 3′ UTR of the Foxp3 mRNA. We show that Foxp3 gene expression can be directly regulated by miR31. However, our experiments demonstrate that two distinct mechanisms must cooperate to regulate play the global level of expression of FoxP3, one mediated via miR31, and the second one at the promoter site of the gene. This part of the work is still in progress. In conclusion, not only have we found and validated a miR signature for human natural Treg, but we also unveiled some of the mechanisms by which this signature was related to the control of the Foxp3 protein levels in these cells.

scholarly journals IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo

Blood ◽  
2006 ◽  
Vol 108 (5) ◽  
pp. 1571-1579 ◽  
Author(s):  
Emmanuel Zorn ◽  
Erik A. Nelson ◽  
Mehrdad Mohseni ◽  
Fabrice Porcheray ◽  
Haesook Kim ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Nk Cells ◽  
Low Dose ◽  
Fold Increase ◽  
Foxp3 Expression ◽  
Myelogenous Leukemia ◽  
Hematopoietic Stem

IL-2 plays a critical role in the maintenance of CD4+CD25+ FOXP3+ regulatory T cells (Tregs) in vivo. We examined the effects of IL-2 signaling in human Tregs. In vitro, IL-2 selectively up-regulated the expression of FOXP3 in purified CD4+CD25+ T cells but not in CD4+CD25- cells. This regulation involved the binding of STAT3 and STAT5 proteins to a highly conserved STAT-binding site located in the first intron of the FOXP3 gene. We also examined the effects of low-dose IL-2 treatment in 12 patients with metastatic cancer and 9 patients with chronic myelogenous leukemia after allogeneic hematopoietic stem cell transplantation. Overall, IL-2 treatment resulted in a 1.9 median fold increase in the frequency of CD4+CD25+ cells in peripheral blood as well as a 9.7 median fold increase in FOXP3 expression in CD3+ T cells. CD56+CD3- natural killer (NK) cells also expanded during IL-2 therapy but did not express FOXP3. In vitro treatment of NK cells with 5-aza-2′-deoxycytidine restored the IL-2 signaling pathway leading to FOXP3 expression, suggesting that this gene was constitutively repressed by DNA methylation in these cells. Our findings support the clinical evaluation of low-dose IL-2 to selectively modulate CD4+CD25+ Tregs and increase expression of FOXP3 in vivo.

scholarly journals Secretome screening reveals immunomodulating functions of IFNα-7, PAP and GDF-7 on regulatory T-cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mei Ding ◽  
Rajneesh Malhotra ◽  
Tomas Ottosson ◽  
Magnus Lundqvist ◽  
Aman Mebrahtu ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cell Function ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Secreted Proteins ◽  
External Stimulation ◽  
Marker Proteins ◽  
Positive Regulators ◽  
Conformational Model

AbstractRegulatory T cells (Tregs) are the key cells regulating peripheral autoreactive T lymphocytes. Tregs exert their function by suppressing effector T cells. Tregs have been shown to play essential roles in the control of a variety of physiological and pathological immune responses. However, Tregs are unstable and can lose the expression of FOXP3 and suppressive functions as a consequence of outer stimuli. Available literature suggests that secreted proteins regulate Treg functional states, such as differentiation, proliferation and suppressive function. Identification of secreted proteins that affect Treg cell function are highly interesting for both therapeutic and diagnostic purposes in either hyperactive or immunosuppressed populations. Here, we report a phenotypic screening of a human secretome library in human Treg cells utilising a high throughput flow cytometry technology. Screening a library of 575 secreted proteins allowed us to identify proteins stabilising or destabilising the Treg phenotype as suggested by changes in expression of Treg marker proteins FOXP3 and/or CTLA4. Four proteins including GDF-7, IL-10, PAP and IFNα-7 were identified as positive regulators that increased FOXP3 and/or CTLA4 expression. PAP is a phosphatase. A catalytic-dead version of the protein did not induce an increase in FOXP3 expression. Ten interferon proteins were identified as negative regulators that reduced the expression of both CTLA4 and FOXP3, without affecting cell viability. A transcriptomics analysis supported the differential effect on Tregs of IFNα-7 versus other IFNα proteins, indicating differences in JAK/STAT signaling. A conformational model experiment confirmed a tenfold reduction in IFNAR-mediated ISG transcription for IFNα-7 compared to IFNα-10. This further strengthened the theory of a shift in downstream messaging upon external stimulation. As a summary, we have identified four positive regulators of FOXP3 and/or CTLA4 expression. Further exploration of these Treg modulators and their method of action has the potential to aid the discovery of novel therapies for both autoimmune and infectious diseases as well as for cancer.

scholarly journals Low-dose IL-2 therapy limits the reduction in absolute numbers of circulating regulatory T cells in rheumatoid arthritis

2021 ◽  
Vol 13 ◽  
pp. 1759720X2110113
Author(s):  
Sheng-Xiao Zhang ◽  
Jia Wang ◽  
Cai-Hong Wang ◽  
Rui-Huan Jia ◽  
Ming Yan ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Side Effects ◽  
Regulatory T Cells ◽  
Disease Activity ◽  
Immune Tolerance ◽  
Low Dose ◽  
Fold Increase ◽  
Plain Language ◽  
T Subsets

Background: Circulating regulatory T cells (Tregs) are responsible for mediating immune tolerance and maintaining immunological homeostasis. Decreases in Tregs may be involved in the onset of rheumatoid arthritis (RA). Low-dose interleukin-2 (IL-2) has been considered for the treatment of inflammatory diseases mediated by T cells. This study focused on the status of circulating CD4+T subsets and the clinical feasibility of IL-2 therapies in patients with RA. Methods: The subjects included 888 patients with RA and 100 healthy controls (HCs); 233 RA patients received IL-2 treatment with 0.5 million international units (MIU)/day from days 1 through 5. The demographic features, disease activity, and levels of CD4+T cells measured by modified flow cytometry were collected in all RA patients before and after treatment. Results: RA patients had lower absolute Treg counts (but not Th17) compared with HCs, which was associated with disease activity; previously treated RA patients had the fewest circulating Tregs ( p < 0.05). Patients treated with low-dose IL-2 had a three-fold increase in absolute anti-inflammatory Treg counts, as well as a two-fold increase in the other CD4+T subsets. Moreover, post-treatment levels of markers of disease activity in RA patients treated with IL-2 were significantly lower than the baseline values ( p < 0.001), with no apparent side effects. Conclusion: Decreased absolute counts of circulating CD4+T lymphocyte subsets were observed in patients with RA. Circulating Tregs, which mediate immune tolerance, may be involved in the pathogenesis and progression of RA; however, this was ameliorated by low-dose IL-2, without obvious side effects. Plain language summary Low-dose IL-2 treatment for rheumatoid arthritis • Circulating Tregs may be involved in the pathogenesis and progression of RA. • The absolute count of Tregs was significantly correlated with disease activity measures. • Low-dose IL-2 was able to effectively expade Tregs and help for RA patients’ symptoms remission without evaluated side effects.

scholarly journals CD38 Correlates with an Immunosuppressive Treg Phenotype in Lupus-Prone Mice

2021 ◽  
Vol 22 (21) ◽  
pp. 11977
Author(s):  
Jocelyn C. Pérez-Lara ◽  
Enrique Espinosa ◽  
Leopoldo Santos-Argumedo ◽  
Héctor Romero-Ramírez ◽  
Gabriela López-Herrera ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Activation ◽  
Lupus Erythematosus ◽  
Clinical Signs ◽  
Foxp3 Expression ◽  
Cell Receptor ◽  
Treg Cells ◽  
Transmembrane Glycoprotein ◽  
Ifn Γ

CD38 is a transmembrane glycoprotein expressed by T-cells. It has been reported that patients with systemic lupus erythematosus (SLE) showed increased CD38+CD25+ T-cells correlating with immune activation and clinical signs. Contrariwise, CD38 deficiency in murine models has shown enhanced autoimmunity development. Recent studies have suggested that CD38+ regulatory T-cells are more suppressive than CD38− regulatory T-cells. Thus, we have suggested that CD38 overexpression in SLE patients could play a role in regulating immune activation cells instead of enhancing it. This study found a correlation between CD38 with FoxP3 expression and immunosuppressive molecules (CD69, IL-10, CTLA-4, and PD-1) in T-cells from lupus-prone mice (B6.MRL-Faslpr/J). Additionally, B6.MRL-Faslpr/J mice showed a decreased proportion of CD38+ Treg cells regarding wild-type mice (WT). Furthermore, Regulatory T-Cells (Treg cells) from CD38-/- mice showed impairment in expressing immunosuppressive molecules and proliferation after stimulation through the T-cell receptor (TCR). Finally, we demonstrated an increased ratio of IFN-γ/IL-10 secretion in CD38-/- splenocytes stimulated with anti-CD3 compared with the WT. Altogether, our data suggest that CD38 represents an element in maintaining activated and proliferative Treg cells. Consequently, CD38 could have a crucial role in immune tolerance, preventing SLE development through Treg cells.

scholarly journals Blockade of interleukin-27 signaling reduces GVHD in mice by augmenting Treg reconstitution and stabilizing Foxp3 expression

Blood ◽  
2016 ◽  
Vol 128 (16) ◽  
pp. 2068-2082 ◽  
Author(s):  
Ludovic Belle ◽  
Kimberle Agle ◽  
Vivian Zhou ◽  
Cheng Yin-Yuan ◽  
Richard Komorowski ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
Regulatory T Cells ◽  
Foxp3 Expression ◽  
Interleukin 27 ◽  
Key Points ◽  
The Stability

Key Points Blockade of IL-27 signaling mitigates the severity of GVHD by recalibrating the effector and regulatory arms of the immune system. Inhibition of IL-27 augments the reconstitution of CD4+ and CD8+ regulatory T cells and increases the stability of Foxp3 expression.

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