Expansion of peripheral naturally occurring T regulatory cells by Fms-like tyrosine kinase 3 ligand treatment
Expansion of peripheral naturally occurring T regulatory cells by Fms-like tyrosine kinase 3 ligand treatment
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DOI：
10.1182/blood-2008-06-161026
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发表时间：
2009-06-18
期刊：
影响因子：
20.3
通讯作者：
Rolink, Antonius
中科院分区：
文献类型：
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作者：
Swee, Lee Kim;Bosco, Nabil;Rolink, Antonius
Fms样酪氨酸激酶3配体（FLT3L）在树突状细胞（DC）生物学中起主要作用。FLT3L缺乏会导致DC数量急剧减少，而增加其可利用性（通过重复注射7 - 10天）会使DC数量增加10倍。在本研究中，我们表明FLT3L治疗间接导致外周天然存在的调节性T细胞（NTregs）扩增。在切除胸腺的小鼠中仍能观察到FLT3L诱导的NTregs增加，这排除了胸腺在该机制中的作用。相反，NTregs数量增加是由于预先存在的NTregs增殖，很可能是由于与数量增加的DCs相互作用更有利。在体外，我们表明DCs通过直接细胞接触以及白细胞介素 - 2依赖、T细胞受体非依赖的方式诱导调节性T细胞（Treg）增殖。FLT3L能够预防急性移植物抗宿主病（GVHD）所致的死亡。本研究展示了DCs对调节性T细胞稳态调节的独特方面，这些方面在此之前未被重视。它还通过FLT3L增加致耐受性DCs和NTregs数量的能力，强化了FLT3L治疗在GVHD中的相关性。（《血液》2009年；113卷：6277 - 6287页）
Fms-like tyrosine kinase 3 ligand (FLT3L) plays a major role in dendritic cell (DC) biology. Deficiency of FLT3L causes a dramatic decrease in DC numbers, whereas increasing its availability (by repetitive injections for 7-10 days) leads to a 10-fold increase in DC numbers. In this study, we show that FLT3L treatment indirectly leads to an expansion of peripheral naturally occurring T regulatory cells (NTregs). The FLT3L-induced increase in NTregs was still observed in thymectomized mice, ruling out the role of the thymus in this mechanism. Instead, the increased number of NTregs was due to proliferation of preexisting NTregs, most likely due to favored interactions with increased number of DCs. In vitro, we show that DCs induce regulatory T-cell (Treg) proliferation by direct cell contact and in an interleukin-2-dependent, T-cell receptor-independent manner. FLT3L could prevent death induced by acute graft-versus-host disease (GVHD). This study demonstrates unique aspects in the regulation of Treg homeostasis by DCs, which were unappreciated until now. It also reinforces the relevance of FLT3L treatment in GVHD by its ability to increase both the number of tolerizing DCs and NTregs. (Blood. 2009; 113: 6277-6287)