Recirculating IL-1R2+ Tregs fine-tune intrathymic Treg development under inflammatory conditions
Recirculating IL-1R2+ Tregs fine-tune intrathymic Treg development under inflammatory conditions
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DOI：
10.1038/s41423-019-0352-8
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发表时间：
2020-01-27
影响因子：
24.1
通讯作者：
Huehn, Jochen
中科院分区：
文献类型：
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作者：
Nikolouli, Eirini;Elfaki, Yassin;Huehn, Jochen
绝大多数 Foxp3(+) 调节性 T 细胞 (Treg) 是在胸腺中产生的，并且已知多种因素，例如细胞因子和独特的胸腺抗原呈递细胞，有助于这些胸腺来源的 Tregs (tTreg) 的发育。在这里，我们报告了胸腺中存在特定的 Foxp3(+) Tregs 子集，其特征是表达 IL-1R2，IL-1R2 是炎症细胞因子 IL-1 的诱饵受体。对Foxp3(hCD2)xRAG1(GFP)报告小鼠的胸腺细胞进行详细的流式细胞分析显示，IL-1R2(+) Tregs主要是RAG1(GFP-)和CCR6(+)CCR7(-)，表明这些Treg是从外周进入胸腺的再循环细胞，并且它们具有激活的表型。在脾脏中，大多数 IL-1R2(+) Tregs 表达 Neuropilin-1 (Nrp-1) 和 Helios，表明这些 Tregs 的胸腺起源。有趣的是，在所有研究的组织中，IL-1R2(+) Tregs 在胸腺中出现频率最高，表明胸腺优先招募该 Treg 子集。利用胎儿胸腺器官培养物（FTOC），我们证明外源性IL-1β浓度的增加会阻碍胸腺内Treg的发育，导致CD25（+）Foxp3（+）tTreg的频率降低和CD25（+）Foxp3（-）Treg前体的积累。有趣的是，向重新聚集的胸腺器官培养物（RTOC）中添加IL-1R2（+）Treg，而不是IL-1R2（-）Treg，消除了IL-1β介导的阻断，表明这些再循环的IL-1R2（+）Treg可以淬灭胸腺中的IL-1信号传导，从而即使在炎症条件下也能维持胸腺Treg发育。
The vast majority of Foxp3(+) regulatory T cells (Tregs) are generated in the thymus, and several factors, such as cytokines and unique thymic antigen-presenting cells, are known to contribute to the development of these thymus-derived Tregs (tTregs). Here, we report the existence of a specific subset of Foxp3(+) Tregs within the thymus that is characterized by the expression of IL-1R2, which is a decoy receptor for the inflammatory cytokine IL-1. Detailed flow cytometric analysis of the thymocytes from Foxp3(hCD2)xRAG1(GFP) reporter mice revealed that the IL-1R2(+) Tregs are mainly RAG1(GFP-) and CCR6(+)CCR7(-), demonstrating that these Tregs are recirculating cells entering the thymus from the periphery and that they have an activated phenotype. In the spleen, the majority of IL-1R2(+) Tregs express neuropilin-1 (Nrp-1) and Helios, suggesting a thymic origin for these Tregs. Interestingly, among all tissues studied, the highest frequency of IL-1R2(+) Tregs was observed in the thymus, indicating preferential recruitment of this Treg subset by the thymus. Using fetal thymic organ cultures (FTOCs), we demonstrated that increased concentrations of exogenous IL-1 beta blocked intrathymic Treg development, resulting in a decreased frequency of CD25(+)Foxp3(+) tTregs and an accumulation of CD25(+)Foxp3(-) Treg precursors. Interestingly, the addition of IL-1R2(+) Tregs, but not IL-1R2(-) Tregs, to reaggregated thymic organ cultures (RTOCs) abrogated the IL-1 beta-mediated blockade, demonstrating that these recirculating IL-1R2(+) Tregs can quench IL-1 signaling in the thymus and thereby maintain thymic Treg development even under inflammatory conditions.