Lineage switch of human B cells to macrophages: relevance to the pathophysiology of Hodgkin lymphoma

我们研究了细胞因子对人血单核细胞分化的调控。当我们开始这项研究时，我们的目的是探讨人类B细胞向巨噬细胞的谱系转换与霍奇金淋巴瘤病理生理学的相关性。在研究过程中，我们偶然发现，人血液单核细胞在暴露于由GM-CSF、TGF-β 1和Notch配体Delta-1（Delta-1）组成的皮肤细胞因子环境时可以产生朗格汉斯细胞。这些朗格汉斯细胞表达CD 1a、E-cadherin、Langerin、CCR 6和Birbeck garanules，所有这些都是朗格汉斯细胞标志物。细胞对MIP-1 α具有吞噬活性和趋化性。响应于CD 40配体和TNF-α，细胞获得成熟表型。细胞反过来表现出对MIP-3 P的趋化性，并引起T细胞的活化。GM-CSF和IL-3的受体共享将信号转导到细胞中的共同β亚基。虽然GM-CSF是由多种细胞产生的， ...更多信息 IL-3在皮肤环境中不是组成型合成的，其细胞来源限于活化的T细胞。由于先前的研究已经证明GM-CSF和IL-3对人血液单核细胞具有相似的活性，我们研究了IL-3是否可以替代GM-CSF从血液单核细胞产生朗格汉斯细胞。当在IL-3、TGF-β 1和Delta-1的存在下培养时，单核细胞没有变成朗格汉斯细胞。然而，向补充有IL-3、TGF-β 1和Delta-1的培养物中添加GM-CSF恢复了单核细胞向朗格汉斯细胞的分化。这些数据表明GM-CSF对于从单核细胞诱导朗格汉斯细胞是必不可少的。微阵列分析显示，与用IL-3、TGF-β 1和Delta-1培养的细胞相比，在用GM-CSF、TGF-β 1和Delta-1培养的细胞中存在一小部分基因，其转录物显著上调，并且该子集包括E-钙粘蛋白和Langerin，它们是朗格汉斯细胞标志物。这些结果强调了皮肤环境在从血液单核细胞发育朗格汉斯细胞中的重要性。少

We have studies the regulation of the differentiation of human blood monocytes by cytokines. When we began this study, our objective was to explore the relevance of lineage switch of human B cells to macrophages to the pathophysiology of Hodgkin lymphoma. During the study, we incidentally found that human blood monocytes can give rise to Langerhans cells upon exposure to the skin cytokine environment consisting of GM-CSF, TGF-pi, and Notch ligand Delta-1 (Delta-1). These Langerhans cells expressed CD1a, E-cadherin, Langerin, CCR6, and Birbeck garanules, all of which are Langerhans cell markers. The cells displayed phagocytic activity and chemotaxis to MlP-la. In response to CD40 ligand and TNF-a, the cells acquired a mature phenotype. The cells in turn showed chemotaxis toward MIP-3P and elicited activation of T cells. The receptors for GM-CSF and IL-3 share a common (3 subunit that transduces the signals into cells. While GM-CSF is produced by a variety of cells that populate the skin … More , IL-3 is not constitutively synthesized in the skin environment and its cellular source is restricted to activated T cells. As previous studies have demonstrated similar activities of GM-CSF and IL-3 on human blood monocytes, we investigated whether IL-3 can replace GM-CSF to generate Langerhans cells from blood monocytes. When cultured in the presence of IL-3, TGF-pi, and Delta-1, monocytes did not become Langerhans cells. However, the addition of GM-CSF to the culture supplemented with IL-3, TGF-pi, and Delta-1 restored the differentiation of monocytes toward Langerhans cells. These data indicate that GM-CSF is indispensable for the induction of Langerhans cells from monocytes. A microarray analysis revealed that there exsited a small subset of genes whose transcripts were significantly up-regulated in the cells cultured with GM-CSF, TGF-pi, and Delta-1 in comparison to those with IL-3, TGF-pi, and Delta-1 and that the subset included E-cadherin and Langerin which are Langerhans cell markers. These results emphasize the importance of the skin environmental milieu in the development of Langerhans cells from blood monocytes. Less