Impact of 5-aza-2'-deoxycytidine and epigallocatechin-3-gallate for induction of human regulatory T cells.

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Hdl Handle:
http://hdl.handle.net/10033/344472
Title:
Impact of 5-aza-2'-deoxycytidine and epigallocatechin-3-gallate for induction of human regulatory T cells.
Authors:
Kehrmann, Jan; Tatura, Roman; Zeschnigk, Michael; Probst-Kepper, Michael; Geffers, Robert ( 0000-0003-4409-016X ) ; Steinmann, Joerg; Buer, Jan
Abstract:
The epigenetic regulation of transcription factor genes is critical for T-cell lineage specification. A specific methylation pattern within a conserved region of the lineage specifying transcription factor gene FOXP3, the Treg-specific demethylated region (TSDR), is restricted to regulatory T (Treg) cells and is required for stable expression of FOXP3 and suppressive function. We analysed the impact of hypomethylating agents 5-aza-2'-deoxycytidine and epigallocatechin-3-gallate on human CD4(+)  CD25(-) T cells for generating demethylation within FOXP3-TSDR and inducing functional Treg cells. Gene expression, including lineage-specifying transcription factors of the major T-cell lineages and their leading cytokines, functional properties and global transcriptome changes were analysed. The FOXP3-TSDR methylation pattern was determined by using deep amplicon bisulphite sequencing. 5-aza-2'-deoxycytidine induced FOXP3-TSDR hypomethylation and expression of the Treg-cell-specific genes FOXP3 and LRRC32. Proliferation of 5-aza-2'-deoxycytidine-treated cells was reduced, but the cells did not show suppressive function. Hypomethylation was not restricted to FOXP3-TSDR and expression of master transcription factors and leading cytokines of T helper type 1 and type 17 cells were induced. Epigallocatechin-3-gallate induced global DNA hypomethylation to a lesser extent than 5-aza-2'-deoxycitidine, but no relevant hypomethylation within FOXP3-TSDR or expression of Treg-cell-specific genes. Neither of the DNA methyltransferase inhibitors induced fully functional human Treg cells. 5-aza-2'-deoxycitidine-treated cells resembled Treg cells, but they did not suppress proliferation of responder cells, which is an essential capability to be used for Treg cell transfer therapy. Using a recently developed targeted demethylation technology might be a more promising approach for the generation of functional Treg cells.
Affiliation:
Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Germany.
Citation:
Impact of 5-aza-2'-deoxycytidine and epigallocatechin-3-gallate for induction of human regulatory T cells. 2014, 142 (3):384-95 Immunology
Journal:
Immunology
Issue Date:
Jul-2014
URI:
http://hdl.handle.net/10033/344472
DOI:
10.1111/imm.12261
PubMed ID:
24476360
Type:
Article
Language:
en
ISSN:
1365-2567
Appears in Collections:
publications of the research group genomeanalytics (GMAK)

Full metadata record

DC FieldValue Language
dc.contributor.authorKehrmann, Janen
dc.contributor.authorTatura, Romanen
dc.contributor.authorZeschnigk, Michaelen
dc.contributor.authorProbst-Kepper, Michaelen
dc.contributor.authorGeffers, Roberten
dc.contributor.authorSteinmann, Joergen
dc.contributor.authorBuer, Janen
dc.date.accessioned2015-02-16T13:39:43Zen
dc.date.available2015-02-16T13:39:43Zen
dc.date.issued2014-07en
dc.identifier.citationImpact of 5-aza-2'-deoxycytidine and epigallocatechin-3-gallate for induction of human regulatory T cells. 2014, 142 (3):384-95 Immunologyen
dc.identifier.issn1365-2567en
dc.identifier.pmid24476360en
dc.identifier.doi10.1111/imm.12261en
dc.identifier.urihttp://hdl.handle.net/10033/344472en
dc.description.abstractThe epigenetic regulation of transcription factor genes is critical for T-cell lineage specification. A specific methylation pattern within a conserved region of the lineage specifying transcription factor gene FOXP3, the Treg-specific demethylated region (TSDR), is restricted to regulatory T (Treg) cells and is required for stable expression of FOXP3 and suppressive function. We analysed the impact of hypomethylating agents 5-aza-2'-deoxycytidine and epigallocatechin-3-gallate on human CD4(+)  CD25(-) T cells for generating demethylation within FOXP3-TSDR and inducing functional Treg cells. Gene expression, including lineage-specifying transcription factors of the major T-cell lineages and their leading cytokines, functional properties and global transcriptome changes were analysed. The FOXP3-TSDR methylation pattern was determined by using deep amplicon bisulphite sequencing. 5-aza-2'-deoxycytidine induced FOXP3-TSDR hypomethylation and expression of the Treg-cell-specific genes FOXP3 and LRRC32. Proliferation of 5-aza-2'-deoxycytidine-treated cells was reduced, but the cells did not show suppressive function. Hypomethylation was not restricted to FOXP3-TSDR and expression of master transcription factors and leading cytokines of T helper type 1 and type 17 cells were induced. Epigallocatechin-3-gallate induced global DNA hypomethylation to a lesser extent than 5-aza-2'-deoxycitidine, but no relevant hypomethylation within FOXP3-TSDR or expression of Treg-cell-specific genes. Neither of the DNA methyltransferase inhibitors induced fully functional human Treg cells. 5-aza-2'-deoxycitidine-treated cells resembled Treg cells, but they did not suppress proliferation of responder cells, which is an essential capability to be used for Treg cell transfer therapy. Using a recently developed targeted demethylation technology might be a more promising approach for the generation of functional Treg cells.en
dc.language.isoenen
dc.subject.meshAzacitidineen
dc.subject.meshCatechinen
dc.subject.meshForkhead Transcription Factorsen
dc.subject.meshHumansen
dc.subject.meshMaleen
dc.subject.meshMethylationen
dc.subject.meshOligonucleotide Array Sequence Analysisen
dc.subject.meshT-Lymphocytes, Regulatoryen
dc.titleImpact of 5-aza-2'-deoxycytidine and epigallocatechin-3-gallate for induction of human regulatory T cells.en
dc.typeArticleen
dc.contributor.departmentInstitute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Germany.en
dc.identifier.journalImmunologyen

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