Unique properties of thymic antigen-presenting cells promote epigenetic imprinting of alloantigen-specific regulatory T cells.
Unique properties of thymic antigen-presenting cells promote epigenetic imprinting of alloantigen-specific regulatory T cells.
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DOI：
10.18632/oncotarget.16221
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发表时间：
2017-05-30
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影响因子：
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通讯作者：
Huehn J
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作者：
Garg G;Nikolouli E;Hardtke-Wolenski M;Toker A;Ohkura N;Beckstette M;Miyao T;Geffers R;Floess S;Gerdes N;Lutgens E;Osterloh A;Hori S;Sakaguchi S;Jaeckel E;Huehn J
调节性T细胞（Regulatory T cells，Tcells）是诱导移植耐受的潜在免疫候选细胞。然而，TdR的稳定性仍然存在争议，可能会限制其临床应用。最近的工作表明，Foxp 3和其他Treg特异性标签基因的表观遗传印记对于Foxp 3 + Treg的免疫抑制特性的稳定是至关重要的，并且这些事件已经在胸腺Treg发育的早期阶段开始。然而，控制这一过程的机制在很大程度上仍然未知。在这里，我们证明，胸腺抗原呈递细胞（APC），包括胸腺树突状细胞（t-DCs）和胸腺髓质上皮细胞（mTECs），可以诱导更明显的Foxp 3和其他Treg特异性表观遗传标记基因的脱甲基化，在发展TCLT相比，脾DCs（SP-DCs）。APC的转录组学分析揭示了分泌因子和共刺激分子的差异表达，然而，无论是加入条件培养基，也不干扰共刺激信号影响Foxp 3诱导胸腺APC在体外。重要的是，当在体内测试时，mTEC-和t-DC-产生的同种异体抗原特异性TCLs在延长皮肤同种异体移植物接受方面显示出比sp-DC产生的TCLs显著更高的功效。我们的研究结果引起了人们对胸腺APCs在启动稳定和功能性THBE的承诺方面的独特特性的关注，这一发现可能在临床免疫治疗中非常有益。
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.