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Impact of 5-aza-2′-deoxycytidine and epigallocatechin-3-gallate for induction of human regulatory T cells.
- Source :
-
Immunology . Jul2014, Vol. 142 Issue 3, p384-395. 12p. - Publication Year :
- 2014
-
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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00192805
- Volume :
- 142
- Issue :
- 3
- Database :
- Academic Search Index
- Journal :
- Immunology
- Publication Type :
- Academic Journal
- Accession number :
- 96395709
- Full Text :
- https://doi.org/10.1111/imm.12261