Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-Machi, Maebashi, Gunma 371-8512, Japan.
Immunol Lett. 2011 Mar 30;135(1-2):100-7. doi: 10.1016/j.imlet.2010.10.004. Epub 2010 Oct 16.
Signal regulatory protein α (SIRPα) is an immunoglobulin superfamily protein that is predominantly expressed in dendritic cells (DCs). Its cytoplasmic region binds SHP-1 or SHP-2 protein tyrosine phosphatases, while its extracellular region interacts with CD47, another immunoglobulin superfamily protein, constituting cell-cell signaling. SIRPα was previously shown to be important for development of contact hypersensitivity, likely as a result of its positive regulation of the priming by DCs of CD4(+) T cells. However, the mechanism by which SIRPα regulates DC functions remains unknown. Here we found that the number of I-A(+) cells, which represent migratory DCs such as Langerhans cells (LCs) or dermal DCs from the skin, in the peripheral lymph nodes (LNs) was markedly decreased in mice expressing a mutant form of SIRPα that lacks the cytoplasmic region compared with that of wild-type (WT) mice. In addition, an increase of fluorescein isothiocyanate (FITC)-bearing I-A(+) cells in the draining lymph nodes (LNs) after skin-painting with FITC was markedly blunted in SIRPα mutant mice. However, migratory ability, as well as expression of CCR7, of bone marrow-derived DCs prepared from SIRPα mutant mice were not impaired. By contrast, the number of I-A(+) LCs in the epidermis of SIRPα mutant mice was markedly decreased compared with that of WT mice. In addition, the mRNA expression of transforming growth factor-β receptor II in LCs of SIRPα mutant mice was markedly decreased compared with that of WT mice. These results suggest that SIRPα is important for homeostasis of LCs in the skin, as well as of migratory DCs in the LNs, but unlikely for migration of these cells from the skin to draining LNs.
信号调节蛋白α（SIRPα）是免疫球蛋白超家族蛋白，主要在树突状细胞（DCs）中表达。其胞质区结合 SHP-1 或 SHP-2 蛋白酪氨酸磷酸酶，而其细胞外区与另一种免疫球蛋白超家族蛋白 CD47 相互作用，构成细胞间信号传递。SIRPα 先前被证明对接触超敏反应的发展很重要，可能是因为它对 DC 对 CD4(+)T 细胞的启动具有正调节作用。然而，SIRPα 调节 DC 功能的机制尚不清楚。在这里，我们发现与野生型（WT）小鼠相比，表达缺乏胞质区的 SIRPα 突变体的小鼠外周淋巴结（LNs）中 I-A(+)细胞（代表朗格汉斯细胞（LCs）或皮肤中的真皮 DC 等迁移性 DC）的数量明显减少。此外，皮肤涂抹 FITC 后，引流淋巴结（LNs）中携带荧光素异硫氰酸酯（FITC）的 I-A(+)细胞的增加在 SIRPα 突变小鼠中明显减弱。然而，从 SIRPα 突变小鼠制备的骨髓源性 DC 的迁移能力以及 CCR7 的表达并未受损。相比之下，SIRPα 突变小鼠表皮中 I-A(+)LC 的数量明显少于 WT 小鼠。此外，SIRPα 突变小鼠 LCs 中的转化生长因子-β受体 II 的 mRNA 表达明显低于 WT 小鼠。这些结果表明，SIRPα 对于皮肤中的 LCs 以及 LNs 中的迁移性 DC 的稳态很重要，但对于这些细胞从皮肤向引流 LNs 的迁移可能不重要。
