DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells.
The transcription factor FOXP3 is critical for development and function of regulatory T cells (Treg). Their number and functioning appears to be crucial in the prevention of autoimmunity and allergy, but also to be a negative prognostic marker for various solid tumors. Although expression of the transcription factor FOXP3 currently constitutes the best-known marker for Treg, in humans, transient expression is also observed in activated non-Treg. Extending our recent findings for the murine foxp3 locus, we observed epigenetic modification of several regions in the human FOXP3 locus exclusively occurring in Treg. Importantly, activated conventional CD4(+) T cells and TGF-beta-treated cells displayed no FOXP3 DNA demethylation despite expression of FOXP3, whereas subsets of Treg stable even upon extended in vitro expansion remained demethylated. To investigate whether a whole set of genes might be epigenetically imprinted in the Treg lineage, we conducted a genome-wide differential methylation hybridization analysis. Several genes were found displaying differential methylation between Treg and conventional T cells, but none beside FOXP3 turned out to be entirely specific to Treg when tested on a broad panel of cells and tissues. We conclude that FOXP3 DNA demethylation constitutes the most reliable criterion for natural Treg available at present.
Baron
Udo
U
Epiontis GmbH, Berlin, Germany.
Floess
Stefan
S
Wieczorek
Georg
G
Baumann
Katrin
K
Grützkau
Andreas
A
Dong
Jun
J
Thiel
Andreas
A
Boeld
Tina J
TJ
Hoffmann
Petra
P
Edinger
Matthias
M
Türbachova
Ivana
I
Hamann
Alf
A
Olek
Sven
S
Huehn
Jochen
J
D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D019175:DNA Methylation; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D020869:Gene Expression Profiling; D005819:Genetic Markers; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D012680:Sensitivity and Specificity; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology
C487554:CAMTA1 protein, human; D002135:Calcium-Binding Proteins; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D005819:Genetic Markers; D053645:Interleukin-2 Receptor alpha Subunit; D015534:Trans-Activators; D016212:Transforming Growth Factor beta