STAT5 activation underlies IL7 receptor-dependent B cell development
STAT5 activation underlies IL7 receptor-dependent B cell development
复制标题
DOI：
10.4049/jimmunol.172.8.4770
复制
发表时间：
2004-04-15
影响因子：
4.4
通讯作者：
Farrar, MA
中科院分区：
文献类型：
--
作者：
Goetz, CA;Harmon, IR;Farrar, MA
IL7R发起的信号是B细胞开发所必需的。然而，在此过程中不同的IL7R诱导的信号通路在此过程中扮演的角色尚不清楚。为了确定RAF和STAT5途径在IL7R依赖性B细胞发育中的功能，我们使用了在整个淋巴细胞发育中表达RAF（RAF-CAAX）或STAT5（STAT5B-CA）组成型活性形式的转基因小鼠。 RAF-CAAX和Stam-Ca小鼠在Pro-B细胞中均显示出很大的增加。但是，将RAF-CAAX转基因越过IL7R（ - / - ）背景无法挽救B细胞的发育。相反，STAT5激活选择性恢复IL7R（ - / - ）小鼠中的B细胞扩展。值得注意的是，STAT5B-CA小鼠中Pro-B细胞的膨胀与细胞周期蛋白D2，PIM-1和BCL-X（L）表达的增加相关，这表明STAT5直接影响Pro-B细胞的增殖和存活率。此外，STAT5激活还恢复了通过1）恢复V-H Ig基因重排的IL7R（ - / - ）小鼠的B细胞分化，并且2）2）未成熟和成熟的B细胞子集的出现。这些发现将STAT5确定为IL7R下游纳入B细胞开发的关键参与者。
Signals initiated by the IL7R are required for B cell development. However, the roles that distinct IL7R-induced signaling pathways play in this process remains unclear. To identify the function of the Raf and STAT5 pathways in IL7R-dependent B cell development, we used transgenic mice that express constitutively active forms of Raf (Raf-CAAX) or STAT5 (STAT5b-CA) throughout lymphocyte development. Both Raf-CAAX and STAM-CA mice exhibit large increases in pro-B cells. However, crossing the Raf-CAAX transgene onto the IL7R(-/-) background fails to rescue B cell development. In contrast, STAT5 activation selectively restores B cell expansion in IL7R(-/-) mice. Notably, the expansion of pro-B cells in STAT5b-CA mice correlated with an increase in cyclin D2, pim-1, and bcl-x(L) expression, suggesting that STAT5 directly affects pro-B cell proliferation and survival. In addition, STAT5 activation also restored B cell differentiation in IL7R(-/-) mice as determined by 1) the restoration of V-H Ig gene rearrangement and 2) the appearance of immature and mature B cell subsets. These findings establish STAT5 as the key player entraining B cell development downstream of the IL7R.