Heinz Leonhard X, Platzer Barbara, Reisner Peter M, Jörgl Almut, Taschner Sabine, Göbel Florian, Strobl Herbert
Institute of Immunology, Medical University Vienna, Lazarettgasse 19; A-1090 Vienna, Austria.
Blood. 2006 Feb 15;107(4):1445-53. doi: 10.1182/blood-2005-04-1721. Epub 2005 Oct 13.
Langerhans cells (LCs) are highly abundant dendritic cells (DCs) in epidermal and mucosal tissues. The transcription factors PU.1 and Id2 have been implicated as positive regulators of LC development from hematopoietic progenitor cells. LC differentiation from progenitors is absolutely dependent on transforming growth factor beta 1 (TGF-beta1) in vitro as well as in vivo; however, downstream mechanisms are poorly defined. We found that both PU.1 and Id2 are induced by TGF-beta1 in human CD34+ monocyte/LC (M/LC) progenitor cells, and that neither ectopic PU.1 or Id2 alone, nor both together, could replace TGF-beta1 in its instructive function on LC commitment. However, both factors critically contributed to LC differentiation by acting at 2 distinct intersection points. Ectopic PU.1 strongly enhanced TGF-beta1-dependent LC development. Additionally, Notch-induced generation of interstitial-type DCs was associated with PU.1 up-regulation. Thus, PU.1 is generally increased during myeloid DC development. Ectopic Id2 inhibits the acquisition of early monocytic characteristics by cells generated in the absence of TGF-beta1 and also inhibits monocyte induction by alternative stimuli. Since TGF-beta1 represses a default monocyte pathway of common progenitor cells, PU.1 and Id2 seem to modulate lineage options of M/LC precursors, downstream of TGF-beta1.
朗格汉斯细胞（LCs）是表皮和黏膜组织中高度丰富的树突状细胞（DCs）。转录因子PU.1和Id2被认为是造血祖细胞向LC发育的正向调节因子。祖细胞向LC的分化在体外和体内都绝对依赖于转化生长因子β1（TGF-β1）；然而，其下游机制尚不清楚。我们发现，在人CD34+单核细胞/LC（M/LC）祖细胞中，PU.1和Id2均由TGF-β1诱导产生，而且单独异位表达PU.1或Id2，或两者共同异位表达，都不能替代TGF-β1在LC定向分化中的指导作用。然而，这两种因子通过作用于两个不同的交叉点对LC分化起到关键作用。异位表达的PU.1强烈增强了TGF-β1依赖的LC发育。此外，Notch诱导的间质型DCs的产生与PU.1上调有关。因此，在髓样DC发育过程中，PU.1总体上是增加的。异位表达的Id2抑制了在没有TGF-β1的情况下产生的细胞获得早期单核细胞特征，也抑制了其他刺激诱导的单核细胞生成。由于TGF-β1抑制了共同祖细胞的默认单核细胞途径，PU.1和Id2似乎在TGF-β1下游调节M/LC前体细胞的谱系选择。
