A novel role for Notch ligand Delta-1 as a regulator of human Langerhans cell development from blood monocytes
A novel role for Notch ligand Delta-1 as a regulator of human Langerhans cell development from blood monocytes
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DOI：
10.1189/jlb.1204746
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发表时间：
2005-10-01
影响因子：
5.5
通讯作者：
Shiku, H
中科院分区：
文献类型：
--
作者：
Hoshino, N;Katayama, N;Shiku, H
人类朗格汉斯细胞（LC）是造血起源，但其发展的细胞因子调控尚未完全了解。Notch配体Delta-1在一定比例的皮肤中表达。粒细胞-巨噬细胞集落刺激因子（GM-CSF）和转化生长因子-β 1（TGF-β 1）也在皮肤中分泌。我们在此报道Delta-1与GM-CSF和TGF-β 1共同诱导人CD 14（+）血单核细胞分化为表达LC标志物的细胞：CD 1a、Langerin、皮肤淋巴细胞相关抗原、CC趋化因子受体6、E-cadherin和Birbeck颗粒。所得细胞显示吞噬活性和对巨噬细胞炎性蛋白-1 α（MIP-1 α）的趋化性。响应于CD 40配体和肿瘤坏死因子α，细胞获得树突状细胞的成熟表型，其特征在于人白细胞抗原（HLA）-ABC、HLA-DR、CD 80、CD 86、CD 40和CD 54的上调以及CD 83的出现。这些细胞反过来表现出对MIP-1 β的趋化性，并引发CD 8（+）T细胞的活化和CD 4（+）T细胞的T辅助细胞1型极化。因此，血液单核细胞在暴露于由Delta-1、GM-CSF和TGF-β 1组成的皮肤细胞因子环境时可产生LC，其可能部分地与人表皮LC的发育相关。我们的研究结果扩展了Notch配体delta-1在人类造血中的功能范围。
Human Langerhans cells (LCs) are of hematopoietic origin, but cytokine regulation of their development is not fully understood. Notch ligand Delta-1 is expressed in a proportion of the skin. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor-beta 1 (TGF-beta 1) are also secreted in the skin. We report here that Delta-1, in concert with GM-CSF and TGF-beta 1, induces the differentiation of human CD14(+) blood monocytes into cells that express LC markers: CD1a, Langerin, cutaneous lymphocyte-associated antigen, CC chemokine receptor 6, E-cadherin, and Birbeck granules. The resulting cells display phagocytic activity and chemotaxis to macrophage inflammatory protein-1 alpha (MIP-1 alpha). In response to CD40 ligand and tumor necrosis factor alpha, the cells acquire a mature phenotype of dendritic cells that is characterized by up-regulation of human leukocyte antigen (HLA)-ABC, HLA-DR, CD80, CD86, CD40, and CD54 and appearance of CD83. These cells in turn show chemotaxis toward MIP-1 beta and elicit activation of CD8(+) T cells and T helper cell type 1 polarization of CD4(+) T cells. Thus, blood monocytes can give rise to LCs upon exposure to the skin cytokine environment consisting of Delta-1, GM-CSF, and TGF-beta 1, which may be, in part, relevant to the development of human epidermal LCs. Our results extend the functional scope of Notch ligand delta-1 in human hematopoiesis.