DNA Methyltransferase Inhibition Promotes Th1 Polarization in Human CD4+CD25high FOXP3+ Regulatory T Cells but Does Not Affect Their Suppressive Capacity
Regulatory T cells (Treg) can show plasticity whereby FOXP3 expression, the master transcription factor for Treg suppressor function, is lost and proinflammatory cytokines are produced. Optimal FOXP3 expression strongly depends on hypomethylation of the FOXP3 gene. 5-Azacytidine (Aza) and its deriva...
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| Format: | Article |
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2018-01-01
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| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2018/4973964 |
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| author | Sija Landman Marjan Cruijsen Paulo C. M. Urbano Gerwin Huls Piet E. J. van Erp Esther van Rijssen Irma Joosten Hans J. P. M. Koenen |
| author_facet | Sija Landman Marjan Cruijsen Paulo C. M. Urbano Gerwin Huls Piet E. J. van Erp Esther van Rijssen Irma Joosten Hans J. P. M. Koenen |
| author_sort | Sija Landman |
| collection | DOAJ |
| description | Regulatory T cells (Treg) can show plasticity whereby FOXP3 expression, the master transcription factor for Treg suppressor function, is lost and proinflammatory cytokines are produced. Optimal FOXP3 expression strongly depends on hypomethylation of the FOXP3 gene. 5-Azacytidine (Aza) and its derivative 5-aza-2′-deoxycytidine (DAC) are DNA methyltransferase inhibitors (DNMTi) that are therapeutically used in hematological malignancies, which might be an attractive strategy to promote Treg stability. Previous in vitro research primarily focused on Treg induction by DAC from naïve conventional CD4+ T cells (Tconv). Here, we examined the in vitro effect of DAC on the stability and function of FACS-sorted human naturally occurring CD4+CD25high FOXP3+ Treg. We found that in vitro activation of Treg in the presence of DAC led to a significant inhibition of Treg proliferation, but not of Tconv. Although Treg activation in the presence of DAC led to increased IFNγ expression and induction of a Thelper-1 phenotype, the Treg maintained their suppressive capacity. DAC also induced a trend towards increased IL-10 expression. In vivo studies in patients with hematological malignancies that were treated with 5-azacytidine (Vidaza) supported the in vitro findings. In conclusion, despite its potential to increase IFNγ expression, DAC does preserve the suppressor phenotype of naturally occurring Treg. |
| format | Article |
| id | doaj-art-984ed9a899d04d9281cc6f1b53ea3c87 |
| institution | Kabale University |
| issn | 2314-8861 2314-7156 |
| language | English |
| publishDate | 2018-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Immunology Research |
| spelling | doaj-art-984ed9a899d04d9281cc6f1b53ea3c872025-02-03T06:12:17ZengWileyJournal of Immunology Research2314-88612314-71562018-01-01201810.1155/2018/49739644973964DNA Methyltransferase Inhibition Promotes Th1 Polarization in Human CD4+CD25high FOXP3+ Regulatory T Cells but Does Not Affect Their Suppressive CapacitySija Landman0Marjan Cruijsen1Paulo C. M. Urbano2Gerwin Huls3Piet E. J. van Erp4Esther van Rijssen5Irma Joosten6Hans J. P. M. Koenen7Department of Laboratory Medicine-Medical Immunology, Radboud University Medical Center (Radboudumc), Nijmegen, NetherlandsDepartment of Hematology, Radboud University Medical Center (Radboudumc), Nijmegen, NetherlandsDepartment of Laboratory Medicine-Medical Immunology, Radboud University Medical Center (Radboudumc), Nijmegen, NetherlandsDepartment of Hematology, Radboud University Medical Center (Radboudumc), Nijmegen, NetherlandsDepartment of Dermatology, Radboud University Medical Center (Radboudumc), Nijmegen, NetherlandsDepartment of Laboratory Medicine-Medical Immunology, Radboud University Medical Center (Radboudumc), Nijmegen, NetherlandsDepartment of Laboratory Medicine-Medical Immunology, Radboud University Medical Center (Radboudumc), Nijmegen, NetherlandsDepartment of Laboratory Medicine-Medical Immunology, Radboud University Medical Center (Radboudumc), Nijmegen, NetherlandsRegulatory T cells (Treg) can show plasticity whereby FOXP3 expression, the master transcription factor for Treg suppressor function, is lost and proinflammatory cytokines are produced. Optimal FOXP3 expression strongly depends on hypomethylation of the FOXP3 gene. 5-Azacytidine (Aza) and its derivative 5-aza-2′-deoxycytidine (DAC) are DNA methyltransferase inhibitors (DNMTi) that are therapeutically used in hematological malignancies, which might be an attractive strategy to promote Treg stability. Previous in vitro research primarily focused on Treg induction by DAC from naïve conventional CD4+ T cells (Tconv). Here, we examined the in vitro effect of DAC on the stability and function of FACS-sorted human naturally occurring CD4+CD25high FOXP3+ Treg. We found that in vitro activation of Treg in the presence of DAC led to a significant inhibition of Treg proliferation, but not of Tconv. Although Treg activation in the presence of DAC led to increased IFNγ expression and induction of a Thelper-1 phenotype, the Treg maintained their suppressive capacity. DAC also induced a trend towards increased IL-10 expression. In vivo studies in patients with hematological malignancies that were treated with 5-azacytidine (Vidaza) supported the in vitro findings. In conclusion, despite its potential to increase IFNγ expression, DAC does preserve the suppressor phenotype of naturally occurring Treg.http://dx.doi.org/10.1155/2018/4973964 |
| spellingShingle | Sija Landman Marjan Cruijsen Paulo C. M. Urbano Gerwin Huls Piet E. J. van Erp Esther van Rijssen Irma Joosten Hans J. P. M. Koenen DNA Methyltransferase Inhibition Promotes Th1 Polarization in Human CD4+CD25high FOXP3+ Regulatory T Cells but Does Not Affect Their Suppressive Capacity Journal of Immunology Research |
| title | DNA Methyltransferase Inhibition Promotes Th1 Polarization in Human CD4+CD25high FOXP3+ Regulatory T Cells but Does Not Affect Their Suppressive Capacity |
| title_full | DNA Methyltransferase Inhibition Promotes Th1 Polarization in Human CD4+CD25high FOXP3+ Regulatory T Cells but Does Not Affect Their Suppressive Capacity |
| title_fullStr | DNA Methyltransferase Inhibition Promotes Th1 Polarization in Human CD4+CD25high FOXP3+ Regulatory T Cells but Does Not Affect Their Suppressive Capacity |
| title_full_unstemmed | DNA Methyltransferase Inhibition Promotes Th1 Polarization in Human CD4+CD25high FOXP3+ Regulatory T Cells but Does Not Affect Their Suppressive Capacity |
| title_short | DNA Methyltransferase Inhibition Promotes Th1 Polarization in Human CD4+CD25high FOXP3+ Regulatory T Cells but Does Not Affect Their Suppressive Capacity |
| title_sort | dna methyltransferase inhibition promotes th1 polarization in human cd4 cd25high foxp3 regulatory t cells but does not affect their suppressive capacity |
| url | http://dx.doi.org/10.1155/2018/4973964 |
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