Year-end Sale % OFF 
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.
Highlights
CD4+ regulatory T cells (Tregs) - characterized by the expression of the lineage specification factor Foxp3- play an indispensable role for the maintenance of immune homeostasis and self-tolerance [1]
To investigate the role of thymic antigen-presenting cells (APCs), we focused on medullary thymic epithelial cells and thymic dendritic cells (t‐DCs), those APCs that are predominantly found in the thymic medulla, the main hub of Foxp3+ Treg development [37]
We demonstrate that both medullary thymic epithelial cells (mTECs) and t‐DCs have a preferential ability to induce alloantigen-specific Foxp3+ Tregs in vitro when compared to splenic DCs, and to initiate a more pronounced demethylation of the Treg-specific demethylated region (TSDR) and other Treg-specific epigenetic signature genes
Summary
CD4+ regulatory T cells (Tregs) - characterized by the expression of the lineage specification factor Foxp3- play an indispensable role for the maintenance of immune homeostasis and self-tolerance [1]. Selective demethylation of a number of Treg-specific signature genes including Ctla, Gitr, Eos and Helios in addition to the TSDR is crucially required for Foxp3+ T cells to acquire Treg-specific gene expression, lineage stability and full suppressive activity [13, 18, 19]. ITregs with fully methylated Treg-specific epigenetic signature genes display only instable Foxp expression and lack suppressive capacity upon adoptive transfer in vivo [10, 11, 13] Understanding those mechanisms that cause selective demethylation of Treg-specific epigenetic signature genes in developing Tregs could open up ways to manipulate the DNA methylation status of Tregs and allow safe application of in vitro generated Tregs for therapeutic approaches [20]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
