Interleukin-2-mediated inhibition of dendritic cell development correlates with decreased CD135 expression and increased monocyte/macrophage precursors
Interleukin-2-mediated inhibition of dendritic cell development correlates with decreased CD135 expression and increased monocyte/macrophage precursors
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DOI：
10.1111/imm.12345
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发表时间：
2014-12-01
期刊：
影响因子：
6.4
通讯作者：
Tarbell, Kristin V.
中科院分区：
文献类型：
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作者：
Guerrero, Alan D.;Dong, Matthew B.;Tarbell, Kristin V.
我们以前已经表明，白细胞介素-2（IL-2）抑制树突状细胞（DC）的发展与FMS样酪氨酸激酶3受体（Flt 3L）的配体刺激小鼠骨髓（BM）前体，并提供了证据，这种抑制发生在单核细胞DC前体阶段的DC发展。在这里，我们探讨了IL-2介导的DC发育抑制的机制。首先，我们通过比较来自BM、CD 11b（+）和CD 24（+）常规DC（cDC）和浆细胞样DC（pDC）的三种主要Flt 3L诱导的DC亚群与它们各自的离体脾DC亚群（CD 11b（+）、CD 8（+）和pDC）的基因和蛋白表达，证明这些体外培养物准确地模拟了体内发育的DC。接下来，在IL-2存在下发育的Flt 3L DC亚群中定量基因表达变化。这些变化包括Bcl 2l 11的表达增加，其编码凋亡诱导蛋白Bim，以及Flt 3（CD 135）的表达减少，Flt 3（CD 135）是启动DC发育的受体。白细胞介素-2还显著降低了所有三种Flt 3L DC亚群上的Flt 3蛋白表达，并减弱了DC中Flt 3L诱导的STAT 3磷酸化。基于这些数据，我们假设Flt 3信号传导的减少可能使BM前体转移到单核细胞和巨噬细胞谱系。事实上，IL-2的加入导致Flt 3（-）细胞的增加，包括cKit（+）Ly 6C（+）CD 11b（-）群体，与最近鉴定的定向单核细胞/巨噬细胞祖细胞一致。因此，IL-2可以通过减少Flt 3的信号传导和增加单核细胞/巨噬细胞发育来抑制DC发育。
We have previously shown that interleukin-2 (IL-2) inhibits dendritic cell (DC) development from mouse bone marrow (BM) precursors stimulated with the ligand for FMS-like tyrosine kinase 3 receptor (Flt3L), and have provided evidence that this inhibition occurs at the monocyte DC precursor stage of DC development. Here, we explored the mechanism of IL-2-mediated inhibition of DC development. First, we showed that these in vitro cultures accurately model DCs that develop in vivo by comparing gene and protein expression of the three main Flt3L-induced DC subsets from the BM, CD11b(+) and CD24(+) conventional DCs (cDCs) and plasmacytoid DCs (pDCs) with their respective ex vivo spleen DC subsets (CD11b(+), CD8(+) and pDCs). Next, gene expression changes were quantified in Flt3L DC subsets that developed in the presence of IL-2. These changes included increased expression of Bcl2l11, which encodes the apoptosis-inducing protein Bim, and decreased expression of Flt3 (CD135), the receptor that initiates DC development. Interleukin-2 also significantly reduced Flt3 protein expression on all three Flt3L DC subsets, and attenuated Flt3L-induced STAT3 phosphorylation in DCs. Based on these data, we hypothesized that decreased Flt3 signalling may divert BM precursors down monocyte and macrophage lineages. Indeed, addition of IL-2 led to increases in Flt3(-) cells, including cKit(+)Ly6C(+)CD11b(-) populations consistent with the recently identified committed monocyte/macrophage progenitor. Therefore, IL-2 can inhibit DC development via decreased signalling through Flt3 and increased monocyte/macrophage development.