Differentiation of Extrathymic T cells from pluripotent stem cells in the adult mouse liver

在最近的一系列研究中，我们已经证明肝脏是小鼠和人类产生胸腺外T细胞（NKT细胞）的重要免疫器官。这些T细胞与胸腺来源的T细胞的许多特性不同。然而，目前尚不清楚成年小鼠的肝脏是否含有造血干细胞，这些干细胞是否起源于骨髓，以及胸腺外T细胞是否通过循环迁移到其他部位。本课题采用细胞转移实验、联体小鼠和体外培养系统等方法对这一课题进行了研究。1）成年小鼠肝脏中含有c-kit^+干细胞，可以重建受辐射的SCID小鼠的胸腺细胞、多系细胞和骨髓干细胞。这些从肝脏分离的干细胞也在肝脏中产生胸腺外T细胞。2）在联体B6.Ly5.1和B6. Ly5.2小鼠胸腺外T细胞中存在低水平的配偶体细胞混合; 3）从肝脏中分离的c-kite^+干细胞可以通过与肝脏基质细胞共培养产生胸腺外T细胞，而从骨髓中分离的干细胞则不能，这些结果强烈表明肝脏中的胸腺外T细胞是由其自身的干细胞在肝脏中产生的。

In a series of recent studies, we have demonstrated that the liver is an important immune organs that produces extrathymic T cells (NKT cells) in mice and humans. These T cells are distinguished from thymus-derived T cells by many properties. However, it was not known whether the liver of adult mice contains hematopietic stem cells, whether such stem cells originate in bone marrow and whether extrathymic T cells migrate to other sites through the circulation. In this project, we investigate this subjects by the methods of cell transfer experiment, parabiotic mice and in vitro culture systems.1) Livers of the adult mice contain c-kit^+ stem cells that can reconstitute thymocytes, multilineage cells and bone marrow stem cells of irradiated SCID mice. These stem cells isolated from the liver generate also extrathymic T cells in the liver.2) In parabiotic B6.Ly5.1 and B6. Ly5.2 mice, the low level of mixing of partner cells is seen in extrathymic T cells of the liver.3) c-kite^+ stem cells isolated from liver can generate the extrathymic T cells by co-culture with liver stromal cells in vitro, whereas stem cells isolated from bone marrow can not.These results strongly suggest that the extrathymic T cells in the liver was generated in the liver from their own stem cells.