The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
Eur J Immunol. 2012 Nov;42(11):2889-900. doi: 10.1002/eji.201242477. Epub 2012 Sep 3.
Fms-like tyrosine kinase 3 ligand (Flt3L) is a major cytokine that drives development of dendritic cells (DCs) under steady state, whereas GM-CSF becomes a prominent influence on differentiation during inflammation. The influence GM-CSF exerts on Flt3L-induced DC development has not been thoroughly examined. Here, we report that GM-CSF alters Flt3L-induced DC development. When BM cells were cultured with both Flt3L and GM-CSF, few CD8⁺ equivalent DCs or plasmacytoid DCs developed compared to cultures supplemented with Flt3L alone. The disappearance of these two cell subsets in GM-CSF + Flt3L culture was not a result of simple inhibition of their development, but a diversion of the original differentiation trajectory to form a new cell population. As a consequence, both DC progeny and their functions were altered. The effect of GM-CSF on DC subset development was confirmed in vivo. First, the CD8⁺ DC numbers were increased under GM-CSF deficiency (when either GM-CSF or its receptor was ablated). Second, this population was decreased under GM-CSF hyperexpression (by transgenesis or by Listeria infection). Our finding that GM-CSF dominantly changes the regulation of DC development in vitro and in vivo has important implications for inflammatory diseases or GM-CSF therapy.
Fms 样酪氨酸激酶 3 配体（Flt3L）是一种主要的细胞因子，可在稳态下驱动树突状细胞（DC）的发育，而 GM-CSF 在炎症期间对分化产生显著影响。GM-CSF 对 Flt3L 诱导的 DC 发育的影响尚未得到彻底研究。在这里，我们报告 GM-CSF 改变了 Flt3L 诱导的 DC 发育。当 BM 细胞与 Flt3L 和 GM-CSF 一起培养时，与单独补充 Flt3L 的培养物相比，很少有 CD8⁺ 等效 DC 或浆细胞样 DC 发育。GM-CSF + Flt3L 培养中这两个细胞亚群的消失不是由于它们发育的简单抑制，而是原始分化轨迹的改变，形成了一个新的细胞群体。因此，DC 后代及其功能都发生了改变。GM-CSF 对 DC 亚群发育的影响在体内得到了证实。首先，在 GM-CSF 缺乏（当 GM-CSF 或其受体缺失时）下，CD8⁺ DC 数量增加。其次，在 GM-CSF 过度表达（通过转基因或李斯特菌感染）下，该群体减少。我们发现 GM-CSF 在体外和体内主要改变了 DC 发育的调节，这对炎症性疾病或 GM-CSF 治疗具有重要意义。
