Unique properties of thymic antigen-presenting cells promote epigenetic imprinting of alloantigen-specific regulatory T cells.

2.50
Hdl Handle:
http://hdl.handle.net/10033/620958
Title:
Unique properties of thymic antigen-presenting cells promote epigenetic imprinting of alloantigen-specific regulatory T cells.
Authors:
Garg, Garima; Nikolouli, Eirini; Hardtke-Wolenski, Matthias; Toker, Aras; Ohkura, Naganari; Beckstette, Michael; Miyao, Takahisa; Geffers, Robert ( 0000-0003-4409-016X ) ; Floess, Stefan; Gerdes, Norbert; Lutgens, Esther; Osterloh, Anke; Hori, Shohei; Sakaguchi, Shimon; Jaeckel, Elmar; Huehn, Jochen
Abstract:
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.
Affiliation:
Helmholtz Centre for infection research, Inhoffenstr.7, 38124 Braunschweig, Germany.
Citation:
Unique properties of thymic antigen-presenting cells promote epigenetic imprinting of alloantigen-specific regulatory T cells. 2017, 8 (22):35542-35557 Oncotarget
Journal:
Oncotarget
Issue Date:
30-May-2017
URI:
http://hdl.handle.net/10033/620958
DOI:
10.18632/oncotarget.16221
PubMed ID:
28415767
Type:
Article
Language:
en
ISSN:
1949-2553
Appears in Collections:
publications of the division experimentelle Immunologie (EXIM)

Full metadata record

DC FieldValue Language
dc.contributor.authorGarg, Garimaen
dc.contributor.authorNikolouli, Eirinien
dc.contributor.authorHardtke-Wolenski, Matthiasen
dc.contributor.authorToker, Arasen
dc.contributor.authorOhkura, Naganarien
dc.contributor.authorBeckstette, Michaelen
dc.contributor.authorMiyao, Takahisaen
dc.contributor.authorGeffers, Roberten
dc.contributor.authorFloess, Stefanen
dc.contributor.authorGerdes, Norberten
dc.contributor.authorLutgens, Estheren
dc.contributor.authorOsterloh, Ankeen
dc.contributor.authorHori, Shoheien
dc.contributor.authorSakaguchi, Shimonen
dc.contributor.authorJaeckel, Elmaren
dc.contributor.authorHuehn, Jochenen
dc.date.accessioned2017-06-19T12:24:50Z-
dc.date.available2017-06-19T12:24:50Z-
dc.date.issued2017-05-30-
dc.identifier.citationUnique properties of thymic antigen-presenting cells promote epigenetic imprinting of alloantigen-specific regulatory T cells. 2017, 8 (22):35542-35557 Oncotargeten
dc.identifier.issn1949-2553-
dc.identifier.pmid28415767-
dc.identifier.doi10.18632/oncotarget.16221-
dc.identifier.urihttp://hdl.handle.net/10033/620958-
dc.description.abstractRegulatory 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.en
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleUnique properties of thymic antigen-presenting cells promote epigenetic imprinting of alloantigen-specific regulatory T cells.en
dc.typeArticleen
dc.contributor.departmentHelmholtz Centre for infection research, Inhoffenstr.7, 38124 Braunschweig, Germany.en
dc.identifier.journalOncotargeten

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