Generation of CD4+ Regulatory T Cells by Retroviral Transduction of CD4+CD25− T Cells Either with the Full-Length or with a Common Exon-2 Negative Variant of Human Foxp3.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3315-3315
Author(s):  
Tuna Mutis ◽  
Leo F. Verdonck ◽  
Tineke Aarts-Riemens ◽  
Maarten Emmelot
Keyword(s):  
T Cells ◽  
Marker Gene ◽  
Retroviral Vectors ◽  
Treg Cells ◽  
Full Length ◽  
Double Knockout ◽  
Exon 2 ◽  
Foxp3 Gene ◽  
Expression Levels

Abstract The forkhead/winged helix transcription factor, Foxp3 is a key element for the differentiation of CD4+CD25+ regulatory T (Treg) cells. While murine Foxp3 gene is expressed as a single full-length transcript, we observed that transcription of human Foxp3 gene usually reveals two different mRNA products with ~ 100 base pair difference. Sequencing of these products revealed that one transcript represents the full-length Foxp3, while the other transcript appears to be an alternative splicing product that lacks the exon-2. Using a specific primer set that amplifies the region between exon-1 and exon-3 we found that both exon-2pos and exon-2neg variants are preferentially expressed in CD4+CD25+ cells with high levels of expression in CD4+CD25hi cells. Analysis of individual Treg clones generated by limiting dilution of CD4+CD25hi cells revealed that both Foxp3 variants are simultaneously expressed in Treg clones. However, quantitative-real time PCR analyses, performed using a primer set that amplifies only the full-length Foxp3 and another set that amplifies both exon-2neg and exon-2pos variants, indicated that expression levels of the full-length Foxp3 gene do not correlate with expression levels of total Foxp3 in individual Treg clones, in PBMC of healthy donors and in leukemia patients after donor lymphocyte infusions. Remarkably, some donors expressed little or no full-length Foxp3 while expressing considerable amounts of total Foxp3, suggesting a predominant expression of the exon-2neg variant in CD4+CD25+ T cells of these donors. To determine the role of individual Foxp3 isoforms in Treg cell-differentiation, the full-length and the exon-2neg variants of the Foxp3 gene were cloned into retroviral vectors and transduced separately into highly purified CD4+CD25− cells. After a brief in vitro culture, T cells transduced with the Foxp3 isoforms were sorted to high purity by flow cytometry using the GFP marker gene and expanded to high quantities by nonspecific stimulation with allogeneic feeder cells, PHA and IL-2. Phenotypical and functional analyses of expanded cells revealed that T cells transduced with both Foxp3 variants expressed high levels of CD25, intacellular CTLA-4 and CD62L; were anergic to stimulation via CD3 and suppressed the CD3/CD28 triggered proliferation of autologous and allogeneic CD4+CD25− cells. These results reveal that both isoforms of human Foxp3 are functionally intact and can convert CD4+CD25− cells into Treg cells. Current efforts are focused on testing the in vivo capacity of in vitro expanded, Foxp3 transduced T cells to prevent Graft versus Host Disease (GvHD) in a xenogeneic model where GvHD is induced by administration of human T cells in Rag2, gamma chain double knockout mice.

scholarly journals The Importance of CD19 Exon 2 for Surface Localization: Closing the Ig-like Loop

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3433-3433 ◽  
Author(s):  
Asen Bagashev ◽  
Elena Sotillo ◽  
Glendon Wu ◽  
Andrei Thomas-Tikhonenko
Keyword(s):  
T Cells ◽  
Plasma Membrane ◽  
Treatment Failure ◽  
B Cell ◽  
B Lymphocytes ◽  
Surface Expression ◽  
Full Length ◽  
Exon 2 ◽  
Surface Localization

Abstract Background: CD19 is a near-universal surface marker of B-cell malignancies. Therefore, it is regarded as a target of choice for various immunotherapies, such as bi-specific T-cell engagers and chimeric antigen receptor-armed T-cells. Although the latter have proven remarkably effective in treating B-cell acute lymphoblastic leukemia (B-ALL), relapses caused by the loss of the CD19 surface epitopes are emerging as a major reason for treatment failure (Maude et al, 2014). However, the molecular mechanisms of epitope loss remain incompletely characterized. Recently, we have identified a novel alternatively spliced CD19 isoform lacking exon2 (Δex2 CD19) (Sotillo et al 2015). Although exon 2 encodes a single conserved N-linked glycosylation site (Asn-86) and two conserved cysteine residues (Cys-38 and Cys-97) responsible for the formation of a disulfide bond (Zhou et al 1991), the function and subcellular localization of the Δex2 isoform remained unknown. Our aim was to identify specific amino acids within exon 2 that are responsible for proper CD19 surface expression. Methods: CD19-null (ΔCD19) derivatives of Nalm6 and 697 B-ALL cell lines were generated using the CRISPR/Cas9 approach. We then reconstituted them with full-length and Δex2 CD19 isoforms, expressed either on their own or as CD19-GFP fusions. Additionally, CD19 N-terminus mutations (ΔSP [no signal peptide], N86A, C97A and N86A/C97A) were introduced in full-length CD19. Transduced cells were analyzed by flow cytometry, confocal microscopy, and western blotting. Glycosylation of the mutants was verified using treatment with swainsonine (Golgi glycosylation inhibitor) and an in vitro de-glycosylation assay. Results: As expected, deletion of the N-terminal signal peptide responsible for the endoplasmic reticulum translocation led to impaired surface expression. Surprisingly, deletion of exon 2 sequences had a similar effect: although up to 10% of Δex2 CD19 was found on the plasma membrane (where it enhanced pre-B-cell receptor signaling), the remainder was largely cytosolic. Furthermore, while the N86A substitution in full-length CD19 did not significantly affect its surface localization, substituting Cys-97 with Ala fully recapitulated the Δex2 cytosolic phenotype. In fact, the C97A mutant appeared to be stuck in the ER and never reach Golgi, since its electrophoretic mobility was not affected by swainsonine. In contrast, its glycosylation in ER was unperturbed, as evidenced by in vitro de-glycosylation assays. Conclusion: The immunoglobulin-like loop connecting Cys-38 and Cys-97 of CD19 is required for its plasma membrane localization. One possible mechanism is the N-termini-mediated interaction with CD81, which is known to be needed to transport CD19 to the cell surface (Matsumoto et al 1993). Maude SL, Frey, N, Shaw, PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, and Grupp SA. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 2014 371:1507-1517. Sotillo E, Barrett D, Bagashev A, Black K, Lanauze C, Oldridge D, Sussman R, Harrington C, Chung EY, Hofmann TJ, Maude SL, Martinez NM, Raman P, Ruella M, Allman D, Jacoby E, Fry T, Barash Y, Lynch KW, Mackall C, Maris J, Grupp SA, and Thomas-Tikhonenko A. Alternative splicing of CD19 mRNA in leukemias escaping CART-19 immunotherapy eliminates the cognate epitope andcontributes to treatment failure. 2015 AACR Annual Meeting, Philadelphia. Zhou LJ, Ord DC, Hughes AL and Tedder TF, Structure and domain organization of the CD19 antigen of human, mouse, and guinea pig B lymphocytes. Conservation of the extensive cytoplasmic domain. J Immunol. 1991 147(4):1424-32 Matsumoto AK, Martin DR, Carter RH, Klickstein LB, Ahearn JM, and Fearon DT Functional dissection of the CD21/CD19/TAPA-1/Leu-13 complex of B lymphocytes. J Exp Med. 1993 178(4):1407-17. Disclosures No relevant conflicts of interest to declare.

mTOR pathway regulates the differentiation of peripheral blood Th2/Treg cell subsets in patients with pemphigus vulgaris

2021 ◽  
Author(s):  
Kuan Lai ◽  
Wenjing Zhang ◽  
Songshan Li ◽  
Zhiwen Zhang ◽  
Shuangde Xie ◽  
...  
Keyword(s):  
T Cells ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Pemphigus Vulgaris ◽  
Treg Cells ◽  
Mtor Pathway ◽  
Cd4 T Cell ◽  
Cell Ratio ◽  
Loss Of Balance

Abstract Pemphigus vulgaris (PV) is a chronic and potentially life-threatening autoimmune blistering disease. Aberrant mTOR pathway activity is involved in many autoimmune diseases. This study investigated the correlation of mTOR pathway (PI3K/AKT/mTOR/p70S6K) activity with the loss of balance in T helper 2/regulatory T (Th2/Treg) cells in the peripheral blood of PV patients. CD4+ T cells were isolated from 15 PV patients and 15 healthy controls (HCs), the ratios of Th2/CD4+ T cells and Treg/CD4+ T cells, the activity of the mTOR pathway (PI3K/AKT/mTOR/p70S6K), the transcription factors and cytokines of Th2 and Treg cells were detected. Primary CD4+ T cells from PV patients were cultured under Th2- or Treg-polarizing conditions with or without rapamycin in vitro. We found that PV patients showed significantly elevated serum IL-4 when compared with HCs, and serum IL-4 level was positively correlated with the titer of anti-Dsg1/3 antibody and disease severity, while the serum TGF-β level was negatively correlated with the titer of anti-Dsg3 antibody and disease severity. Meanwhile, PV patients showed increased Th2/CD4+ T cell ratio; decreased Treg/CD4+ T cell ratio; elevated mRNA of PI3K, AKT, mTOR and protein of PI3K (P85), AKT, p-AKT (Ser473), mTOR, p-mTOR (Ser2448), p-p70S6K (Thr389), GATA3; reduced protein of forkhead box protein 3. Rapamycin inhibited Th2 cell differentiation and promoted Treg cell differentiation in vitro. These data suggest a close association between mTOR pathway activation and the loss of balance in Th2/Treg cells in peripheral blood of PV patients. Inhibiting mTORC1 can help restore the Th2/Treg balance.

scholarly journals Trichostatin A Promotes the Generation and Suppressive Functions of Regulatory T Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Cristian Doñas ◽  
Macarena Fritz ◽  
Valeria Manríquez ◽  
Gabriela Tejón ◽  
María Rosa Bono ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Trichostatin A ◽  
Gene Promoter ◽  
Treg Cells ◽  
Specific Subset ◽  
Global Increase ◽  
And Function ◽  
H3 Acetylation

Regulatory T cells are a specific subset of lymphocytes that suppress immune responses and play a crucial role in the maintenance of self-tolerance. They can be generated in the thymus as well as in the periphery through differentiation of naïve CD4+T cells. The forkhead box P3 transcription factor (Foxp3) is a crucial molecule regulating the generation and function of Tregs. Here we show that thefoxp3gene promoter becomes hyperacetylated inin vitrodifferentiated Tregs compared to naïve CD4+T cells. We also show that the histone deacetylase inhibitor TSA stimulated thein vitrodifferentiation of naïve CD4+T cells into Tregs and that this induction was accompanied by a global increase in histone H3 acetylation. Importantly, we also demonstrated that Tregs generated in the presence of TSA have phenotypical and functional differences from the Tregs generated in the absence of TSA. Thus, TSA-generated Tregs showed increased suppressive activities, which could potentially be explained by a mechanism involving the ectonucleotidases CD39 and CD73. Our data show that TSA could potentially be used to enhance the differentiation and suppressive function of CD4+Foxp3+Treg cells.

IL-7R–dependent survival and differentiation of early T-lineage progenitors is regulated by the BTB/POZ domain transcription factor Miz-1

Blood ◽  
2011 ◽  
Vol 117 (12) ◽  
pp. 3370-3381 ◽  
Author(s):  
Ingrid Saba ◽  
Christian Kosan ◽  
Lothar Vassen ◽  
Tarik Möröy
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Strong Reduction ◽  
Expression Levels ◽  
Cell Numbers ◽  
Finger Protein

Abstract T cells originate from early T lineage precursors that have entered the thymus and differentiate through well-defined steps. Mice deficient for the BTB/POZ domain of zinc finger protein-1 (Miz-1) almost entirely lack early T lineage precursors and have a CD4−CD8− to CD4+CD8+ block causing a strong reduction in thymic cellularity. Miz-1ΔPOZ pro-T cells cannot differentiate in vitro and are unable to relay signals from the interleukin-7R (IL-7R). Both STAT5 phosphorylation and Bcl-2 up-regulation are perturbed. The high expression levels of SOCS1 found in Miz-1ΔPOZ cells probably cause these alterations. Moreover, Miz-1 can bind to the SOCS1 promoter, suggesting that Miz-1 deficiency causes a deregulation of SOCS1. Transgenic overexpression of Bcl-2 or inhibition of SOCS1 restored pro-T cell numbers and their ability to differentiate, supporting the hypothesis that Miz-1 is required for the regulation of the IL-7/IL-7R/STAT5/Bcl-2 signaling pathway by monitoring the expression levels of SOCS1.

scholarly journals T-cell–intrinsic Tif1α/Trim24 regulates IL-1R expression on TH2 cells and TH2 cell-mediated airway allergy

2016 ◽  
Vol 113 (5) ◽  
pp. E568-E576 ◽  
Author(s):  
Jimena Perez-Lloret ◽  
Isobel S. Okoye ◽  
Riccardo Guidi ◽  
Yashaswini Kannan ◽  
Stephanie M. Coomes ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Allergic Diseases ◽  
Treg Cells ◽  
Th2 Cells ◽  
T Helper 2 ◽  
Cytokines And Chemokines ◽  
Th2 Cell

There is a paucity of new therapeutic targets to control allergic reactions and forestall the rising trend of allergic diseases. Although a variety of immune cells contribute to allergy, cytokine-secreting αβ+CD4+ T-helper 2 (TH2) cells orchestrate the type-2–driven immune response in a large proportion of atopic asthmatics. To identify previously unidentified putative targets in pathogenic TH2 cells, we performed in silico analyses of recently published transcriptional data from a wide variety of pathogenic TH cells [Okoye IS, et al. (2014) Proc Natl Acad Sci USA 111(30):E3081–E3090] and identified that transcription intermediary factor 1 regulator-alpha (Tif1α)/tripartite motif-containing 24 (Trim24) was predicted to be active in house dust mite (HDM)- and helminth-elicited Il4gfp+αβ+CD4+ TH2 cells but not in TH1, TH17, or Treg cells. Testing this prediction, we restricted Trim24 deficiency to T cells by using a mixed bone marrow chimera system and found that T-cell–intrinsic Trim24 is essential for HDM-mediated airway allergy and antihelminth immunity. Mechanistically, HDM-elicited Trim24−/− T cells have reduced expression of many TH2 cytokines and chemokines and were predicted to have compromised IL-1–regulated signaling. Following this prediction, we found that Trim24−/− T cells have reduced IL-1 receptor (IL-1R) expression, are refractory to IL-1β–mediated activation in vitro and in vivo, and fail to respond to IL-1β–exacerbated airway allergy. Collectively, these data identify a previously unappreciated Trim24-dependent requirement for IL-1R expression on TH2 cells and an important nonredundant role for T-cell–intrinsic Trim24 in TH2-mediated allergy and antihelminth immunity.

CD4+ Foxp3+ regulatory T cell-mediated immunomodulation by anti-depressants inhibiting acid sphingomyelinase

2018 ◽  
Vol 399 (10) ◽  
pp. 1175-1182 ◽  
Author(s):  
Jürgen Schneider-Schaulies ◽  
Niklas Beyersdorf
Keyword(s):  
T Cells ◽  
T Cell ◽  
Treg Cells ◽  
Tricyclic Antidepressant ◽  
Acid Sphingomyelinase ◽  
Human T Cells ◽  
And Function ◽  
Rate Limiting ◽  
Deficient Mice

AbstractAcid sphingomyelinase (ASM) is the rate-limiting enzyme cleaving sphingomyelin into ceramide and phosphorylcholin. CD4+Foxp3+regulatory T (Treg) cells depend on CD28 signaling for their survival and function, a receptor that activates the ASM. Both, basal and CD28-induced ASM activities are higher in Treg cells than in conventional CD4+T (Tconv) cells. In ASM-deficient (Smpd1−/−) as compared to wt mice, membranes of T cells contain 7–10-fold more sphingomyelin and two- to three-fold more ceramide, and are in a state of higher order than membranes of T cells from wt mice, which may facilitate their activation. Indeed, the frequency of Treg cells among CD4+T cells in ASM-deficient mice and their suppressive activityin vitroare increased. Moreover,in vitrostimulation of ASM-deficient T cells in the presence of TGF-β and IL-2 leads to higher numbers of induced Treg cells. Pharmacological inhibition of the ASM with a clinically used tricyclic antidepressant such as amitriptyline in mice or in tissue culture of murine or human T cells induces higher frequencies of Treg cells among CD4+T cells within a few days. This fast alteration of the balance between T cell populationsin vitrois due to the elevated cell death of Tconv cells and protection of the CD25highTreg cells by IL-2. Together, these findings suggest that ASM-inhibiting antidepressants, including a fraction of the serotonin re-uptake inhibitors (SSRIs), are moderately immunosuppressive and should be considered for the therapy of inflammatory and autoimmune disorders.

scholarly journals Modulation of Tetraspanin 32 (TSPAN32) Expression in T Cell-Mediated Immune Responses and in Multiple Sclerosis

2019 ◽  
Vol 20 (18) ◽  
pp. 4323 ◽  
Author(s):  
Salvo Danilo Lombardo ◽  
Emanuela Mazzon ◽  
Maria Sofia Basile ◽  
Giorgia Campo ◽  
Federica Corsico ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cancer Metastasis ◽  
Treg Cells ◽  
T Helper ◽  
Autoimmune Encephalomyelitis ◽  
Healthy Donors

Tetraspanins are a conserved family of proteins involved in a number of biological processes including, cell–cell interactions, fertility, cancer metastasis and immune responses. It has previously been shown that TSPAN32 knockout mice have normal hemopoiesis and B-cell responses, but hyperproliferative T cells. Here, we show that TSPAN32 is expressed at higher levels in the lymphoid lineage as compared to myeloid cells. In vitro activation of T helper cells via anti-CD3/CD28 is associated with a significant downregulation of TSPAN32. Interestingly, engagement of CD3 is sufficient to modulate TSPAN32 expression, and its effect is potentiated by costimulation with anti-CD28, but not anti-CTLA4, -ICOS nor -PD1. Accordingly, we measured the transcriptomic levels of TSPAN32 in polarized T cells under Th1 and Th2 conditions and TSPAN32 resulted significantly reduced as compared with unstimulated cells. On the other hand, in Treg cells, TSPAN32 underwent minor changes upon activation. The in vitro data were finally translated into the context of multiple sclerosis (MS). Encephalitogenic T cells from Myelin Oligodendrocyte Glycoprotein (MOG)-Induced Experimental Autoimmune Encephalomyelitis (EAE) mice showed significantly lower levels of TSPAN32 and increased levels of CD9, CD53, CD82 and CD151. Similarly, in vitro-activated circulating CD4 T cells from MS patients showed lower levels of TSPAN32 as compared with cells from healthy donors. Overall, these data suggest an immunoregulatory role for TSPAN32 in T helper immune response and may represent a target of future immunoregulatory therapies for T cell-mediated autoimmune diseases.

scholarly journals Context-Dependent Effect of Glucocorticoids on the Proliferation, Differentiation, and Apoptosis of Regulatory T Cells: A Review of the Empirical Evidence and Clinical Applications

2019 ◽  
Vol 20 (5) ◽  
pp. 1142 ◽  
Author(s):  
Luigi Cari ◽  
Francesca De Rosa ◽  
Giuseppe Nocentini ◽  
Carlo Riccardi
Keyword(s):  
T Cells ◽  
Treg Cell ◽  
Inflammatory Diseases ◽  
Treg Cells ◽  
Cell Number ◽  
Lymphoid Tissues ◽  
Treg Number ◽  
Context Dependent

Glucocorticoids (GCs) are widely used to treat several diseases because of their powerful anti-inflammatory and immunomodulatory effects on immune cells and non-lymphoid tissues. The effects of GCs on T cells are the most relevant in this regard. In this review, we analyze how GCs modulate the survival, maturation, and differentiation of regulatory T (Treg) cell subsets into both murine models and humans. In this way, GCs change the Treg cell number with an impact on the mid-term and long-term efficacy of GC treatment. In vitro studies suggest that the GC-dependent expansion of Treg cells is relevant when they are activated. In agreement with this observation, the GC treatment of patients with established autoimmune, allergic, or (auto)inflammatory diseases causes an expansion of Treg cells. An exception to this appears to be the local GC treatment of psoriatic lesions. Moreover, the effects on Treg number in patients with multiple sclerosis are uncertain. The effects of GCs on Treg cell number in healthy/diseased subjects treated with or exposed to allergens/antigens appear to be context-dependent. Considering the relevance of this effect in the maturation of the immune system (tolerogenic response to antigens), the success of vaccination (including desensitization), and the tolerance to xenografts, the findings must be considered when planning GC treatment.

scholarly journals LPS-Treated Podocytes Polarize Naive CD4+ T Cells into Th17 and Treg Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Da-Hai Yuan ◽  
Yang Jia ◽  
Omar Mohamud Hassan ◽  
Li-Yun Xu ◽  
Xiao-Chuan Wu
Keyword(s):  
T Cells ◽  
Th17 Cells ◽  
Treg Cells ◽  
Mouse Bone Marrow ◽  
Th17 Response ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Th 17 ◽  
Induction Process

Aim. Our study is aimed at investigating whether Lipopolysaccharide- (LPS-) treated podocytes could polarize naive CD4+ T cells into different subsets in vitro. Materials and Methods. Podocytes and mouse bone marrow-derived dendritic cells (BMDCs) were first cultured with 25 μg/ml LPS for 6 hours, respectively. Then, naive CD4+ T cells were cocultured with the LPS-treated podocytes or BMDCs at a ratio of 1 : 1 or 1 : 1 : 1. After 48 hours, we collected the suspended cells and supernatant from all groups to measure T helper (Th)17 cells, regulatory T (Treg) cells, and cytokine concentration. Results. We observed the expression of CD80 and major histocompatibility complex class II molecule (MHC II) in podocytes but did not found the upregulation of them after treating podocytes with LPS. LPS-treated podocytes could induce naive CD4+ T cells to Th17 cells and Treg cells with a higher ratio of Th17/Treg than BMDCs. Possible interaction between podocytes and BMDCs may exist in the induction process of Th17 cells and Treg cells. Conclusion. Our study proved that CD80 and MHC II were constitutively expressed in podocytes but not upregulated by LPS. LPS-treated podocytes could polarize naive CD4+ T cells into Th17 and Treg cells and affect the Th17/Treg balance and may incline to cause a Th17 response.

scholarly journals Androgen receptor modulates Foxp3 expression in CD4+CD25+Foxp3+ regulatory T-cells

2015 ◽  
Vol 26 (15) ◽  
pp. 2845-2857 ◽  
Author(s):  
Magdalena Walecki ◽  
Florian Eisel ◽  
Jörg Klug ◽  
Nelli Baal ◽  
Agnieszka Paradowska-Dogan ◽  
...  
Keyword(s):  
T Cells ◽  
Androgen Receptor ◽  
Treg Cell ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Strong Increase ◽  
Histone H4 ◽  
And Function

CD4+CD25+Foxp3+ regulatory T (Treg) cells are able to inhibit proliferation and cytokine production in effector T-cells and play a major role in immune responses and prevention of autoimmune disease. A master regulator of Treg cell development and function is the transcription factor Foxp3. Several cytokines, such as TGF-β and IL-2, are known to regulate Foxp3 expression as well as methylation of the Foxp3 locus. We demonstrated previously that testosterone treatment induces a strong increase in the Treg cell population both in vivo and in vitro. Therefore we sought to investigate the direct effect of androgens on expression and regulation of Foxp3. We show a significant androgen-dependent increase of Foxp3 expression in human T-cells from women in the ovulatory phase of the menstrual cycle but not from men and identify a functional androgen response element within the Foxp3 locus. Binding of androgen receptor leads to changes in the acetylation status of histone H4, whereas methylation of defined CpG regions in the Foxp3 gene is unaffected. Our results provide novel evidence for a modulatory role of androgens in the differentiation of Treg cells.

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