Differential requirement for IL-2 and IL-15 during bifurcated development of thymic regulatory T cells.
Differential requirement for IL-2 and IL-15 during bifurcated development of thymic regulatory T cells.
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DOI：
10.4049/jimmunol.1402144
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发表时间：
2014-12-01
期刊：
影响因子：
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通讯作者：
Seddon B
中科院分区：
文献类型：
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作者：
Marshall D;Sinclair C;Tung S;Seddon B
胸腺中调节性T细胞（Treg）产生的发育途径尚不完全清楚。在这里，我们用四环素诱导的Zap70转基因重建了Zap70缺陷胸腺细胞的胸腺发育，从而允许对Treg发育进行时间解剖。我们发现Treg以独特的动力学发展，在CD4单阳性（SP）胸腺细胞中首次出现在第4天。公认的CD25+FoxP3+ Treg选择模型表明通过CD25+FoxP3−CD4 SP前体发育。相反，我们的动力学分析揭示了大量CD25−FoxP3+细胞的存在，这些细胞在IL-2的作用下能够高效地成熟为CD25+FoxP3+细胞。CD25−FoxP3+细胞在发育动力学和对自身肽MHC的渴望方面更接近于成熟的Treg细胞。这些种群在发育过程中也表现出对细胞因子的不同需求。CD25−FoxP3+细胞依赖于IL-15，而CD25+FoxP3+的生成特异性地需要IL-2。最后，我们发现IL-2和IL-15在体内有不同的来源。IL-15来源于基质，而IL-2完全来源于造血细胞，依赖于完整的CD4谱系发育，而不是抗原经历细胞或NKT细胞。
The developmental pathways of regulatory T cells (Treg) generation in the thymus are not fully understood. Here, we reconstituted thymic development of Zap70 deficient thymocytes with a tetracycline inducible Zap70 transgene to allow temporal dissection of Treg development. We find that Treg develop with distinctive kinetics, first appearing by day 4 amongst CD4 single positive (SP) thymocytes. Accepted models of CD25+FoxP3+ Treg selection suggest development via CD25+FoxP3− CD4 SP precursors. In contrast, our kinetic analysis revealed the presence of abundant CD25− FoxP3+ cells that are highly efficient at maturing to CD25+FoxP3+ cells in response to IL-2. CD25− FoxP3+ cells more closely resembled mature Treg both with respect to kinetics of development and avidity for self peptide MHC. These population also exhibited distinct requirements for cytokines during their development. CD25−FoxP3+ cells were IL-15 dependent while generation of CD25+FoxP3+ specifically required IL-2. Finally, we found that IL-2 and IL-15 arose from distinct sources in vivo. IL-15 was of stromal origin, while IL-2 was of exclusively from haemopoetic cells that depended on intact CD4 lineage development but not either antigen experienced or NKT cells.