Unique properties of thymic antigen-presenting cells promote epigenetic imprinting of alloantigen-specific regulatory T cells.
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Authors
Garg, GarimaNikolouli, Eirini
Hardtke-Wolenski, Matthias
Toker, Aras
Ohkura, Naganari
Beckstette, Michael
Miyao, Takahisa
Geffers, Robert
Floess, Stefan
Gerdes, Norbert
Lutgens, Esther
Osterloh, Anke
Hori, Shohei
Sakaguchi, Shimon
Jaeckel, Elmar
Huehn, Jochen
Issue Date
2017-05-30
Metadata
Show full item recordAbstract
Regulatory T cells (Tregs) are potential immunotherapeutic candidates to induce transplantation tolerance. However, stability of Tregs still remains contentious and may potentially restrict their clinical use. Recent work suggested that epigenetic imprinting of Foxp3 and other Treg-specific signature genes is crucial for stabilization of immunosuppressive properties of Foxp3+ Tregs, and that these events are initiated already during early stages of thymic Treg development. However, the mechanisms governing this process remain largely unknown. Here we demonstrate that thymic antigen-presenting cells (APCs), including thymic dendritic cells (t-DCs) and medullary thymic epithelial cells (mTECs), can induce a more pronounced demethylation of Foxp3 and other Treg-specific epigenetic signature genes in developing Tregs when compared to splenic DCs (sp-DCs). Transcriptomic profiling of APCs revealed differential expression of secreted factors and costimulatory molecules, however neither addition of conditioned media nor interference with costimulatory signals affected Foxp3 induction by thymic APCs in vitro. Importantly, when tested in vivo both mTEC- and t-DC-generated alloantigen-specific Tregs displayed significantly higher efficacy in prolonging skin allograft acceptance when compared to Tregs generated by sp-DCs. Our results draw attention to unique properties of thymic APCs in initiating commitment towards stable and functional Tregs, a finding that could be highly beneficial in clinical immunotherapy.Citation
Unique properties of thymic antigen-presenting cells promote epigenetic imprinting of alloantigen-specific regulatory T cells. 2017, 8 (22):35542-35557 OncotargetAffiliation
Helmholtz Centre for infection research, Inhoffenstr.7, 38124 Braunschweig, Germany.Journal
OncotargetPubMed ID
28415767Type
ArticleLanguage
enISSN
1949-2553ae974a485f413a2113503eed53cd6c53
10.18632/oncotarget.16221
Scopus Count
The following license files are associated with this item:
- Creative Commons
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by-nc-sa/4.0/
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