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

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.

Recirculating IL-1R2+ Tregs fine-tune intrathymic Treg development under inflammatory conditions

“…Slightly higher frequencies were detected on mTECs and t-DCs isolated from BALB/c mice, suggesting that under steady-state conditions a fraction of thymic APCs can sense IL-1. We previously have reported that Il1a and Il1b mRNA is expressed in the thymus under steady-state conditions with t-DCs showing higher expression levels as compared to mTECs 6 . Here, we analysed the presence of both cytokines in the thymus on protein level using thymic lysates and could demonstrate that under steady-state conditions both IL-1 and IL-1 are present in the thymus, in the range of 5-15 pg/ml (Figure 4b).…”

“…The TCR engagement and co-stimulation critical for Treg induction are provided by unique thymic antigen-presenting cells (APCs). In this respect, the best studied and likely most important thymic APCs for the generation of tTregs are medullary thymic epithelial cells (mTECs) and thymic dendritic cells (t-DCs) [4][5][6] . In addition, common γ-chain cytokines, such as IL-2, are essential for tTreg development [7][8][9][10] , and beyond common γ-chain cytokines, TGF-β was also shown to play a key role 11,12 .…”

Zinc as a Gatekeeper of Immune Function

“…The natural importance and therapeutic benefits of regulatory T cells (Tregs) in preventing auto-immune diseases and transplant rejection is becoming more and more accepted [ 167 ]. One important trigger for Treg development is TGF-β-induced Smad 2/3 signaling, which induces expression of the transcription factor forkhead-box-protein p3 (FoxP3), which is essential for lineage commitment.…”

Influenza A virus-induced thymus atrophy differentially affects dynamics of conventional and regulatory T cell development

“…The narrowing of the TCR repertoire diversity could be a direct consequence of DP thymocyte death or the result of a functional impairment of thymic antigen-presenting cells (APCs) or simply a decrease in their numbers secondary to IAV-induced thymic atrophy. Thymic APCs are well known to critically contribute to tTreg cell development [45][46][47][48][49], and future studies need to unravel if IAVinduced thymus atrophy results in alterations of the thymic dendritic cell and thymic epithelial cell compartment, which finally affect the TCR repertoire diversity of newly generated T cell subsets. Indeed, it was shown in models of accelerated thymus atrophy and thymus atrophy due to aging that the functionality of thymic APCs was negatively influenced, resulting in a reduced ability to present self-antigens, which perturbed negative selection and finally provoked autoimmune phenotypes [50].…”