Dai Xuezhi, Chen Yuhong, Di Lie, Podd Andrew, Li Geqiang, Bunting Kevin D, Hennighausen Lothar, Wen Renren, Wang Demin
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, People's Republic of China.
J Immunol. 2007 Jul 15;179(2):1068-79. doi: 10.4049/jimmunol.179.2.1068.
The two closely related Stat5 (Stat5A and Stat5B) proteins are activated by a broad spectrum of cytokines. However, with the complication of the involvement of Stat5A/5B in stem cell function, the role of Stat5A/5B in the development and function of lymphocytes, especially B cells, is not fully understood. In this study, we demonstrated that Stat5A/5B(-/-) fetal liver cells had severe diminution of B cell progenitors but clearly had myeloid progenitors. Consistently, the mutant fetal liver cells could give rise to hemopoietic progenitors and myeloid cells but not B cells beyond pro-B cell progenitors in lethally irradiated wild-type or Jak3(-/-) mice. Deletion of Stat5A/5B in vitro directly impaired IL-7-mediated B cell expansion. Of note, reintroduction of Stat5A back into Stat5A/5B(-/-) fetal liver cells restored their abilities to develop B cells. Importantly, CD19-Cre-mediated deletion of Stat5A/5B in the B cell compartment specifically impaired early B cell development but not late B cell maturation. Moreover, the B cell-specific deletion of Stat5A/5B did not impair splenic B cell survival, proliferation, and Ig production. Taken together, these data demonstrate that Stat5A/5B directly control IL-7-mediated early B cell development but are not required for B cell maturation and Ig production.
两种密切相关的Stat5蛋白（Stat5A和Stat5B）可被多种细胞因子激活。然而，由于Stat5A/5B参与干细胞功能的情况较为复杂，其在淋巴细胞尤其是B细胞的发育和功能中的作用尚未完全明确。在本研究中，我们发现Stat5A/5B基因敲除的胎肝细胞中B细胞祖细胞严重减少，但髓系祖细胞明显存在。同样，在经致死剂量照射的野生型或Jak3基因敲除小鼠中，突变的胎肝细胞可产生造血祖细胞和髓系细胞，但无法产生超过前B细胞祖细胞阶段的B细胞。体外敲除Stat5A/5B直接损害了IL-7介导的B细胞扩增。值得注意的是，将Stat5A重新导入Stat5A/5B基因敲除的胎肝细胞可恢复其发育B细胞的能力。重要的是，CD19-Cre介导的B细胞区室中Stat5A/5B的缺失特异性损害了早期B细胞发育，但不影响晚期B细胞成熟。此外，B细胞特异性敲除Stat5A/5B并不损害脾脏B细胞的存活、增殖和免疫球蛋白产生。综上所述，这些数据表明Stat5A/5B直接控制IL-7介导的早期B细胞发育，但对B细胞成熟和免疫球蛋白产生并非必需。
