Nonredundant roles for Stat5a/b in directly regulating Foxp3
Nonredundant roles for Stat5a/b in directly regulating Foxp3
复制标题
DOI：
10.1182/blood-2006-11-055756
复制
发表时间：
2007-05-15
期刊：
影响因子：
20.3
通讯作者：
O'Shea, John J.
中科院分区：
文献类型：
--
作者：
Yao, Zhengju;Kanno, Yuka;O'Shea, John J.
STATs(信号转导和转录激活因子)调节T细胞命运的多个方面。T调节(Treg)细胞是限制免疫反应的关键亚群，但Stat5a/b和STAT3对Treg细胞发育的相对重要性一直存在争议。我们观察到STATS(Delta N)小鼠外周CD25(+)CD4(+)T细胞减少；然而，对Treg细胞至关重要的转录因子Foxp3在脾CD4(+)T细胞中的水平正常，尽管胸腺中的Foxp3水平降低。相反，完全缺失Stat5a/b(Stat5(-/-))导致表达CD25或Foxp3的CD4(+)T细胞显著减少。通过降低表达CD4的细胞中的Stat5a/b和使用Stat5(-/-)胎肝细胞进行干细胞移植，证明了这一内在要求。Stat5a/b也是Foxp3体外最佳诱导所必需的，并直接与Foxp3基因结合。T细胞中STAT3的减少不会减少胸腺或脾中Treg细胞的数量；然而，依赖于IL-6的STAT3下调Foxp3是必需的。因此，我们得出结论，STAT5a/b在调节Treg细胞中具有基本的、非冗余的作用，而STAT3和Stat5a/b在Foxp3的调节中似乎具有相反的作用。
Stats (signal transducers and activators of transcription) regulate multiple aspects of T-cell fate. T regulatory (Treg) cells are a critical subset that limits immune responses, but the relative importance of Stat5a/b versus Stat3 for Treg cell development has been contentious. We observed that peripheral CD25(+)CD4(+) T cells were reduced in StatS(Delta N) mice; however, the levels of Foxp3, a transcription factor that is critical for Treg cells, were normal in splenic CD4(+) T cells even though they were reduced in the thymus. In contrast, complete deletion of Stat5a/b (Stat5(-/-)) resulted in dramatic reduction in CD25- or Foxp3-expressing CD4(+) T cells. An intrinsic requirement was demonstrated by reduction of Stat5a/b in CD4-expressing cells and by stem cell transplantation using Stat5(-/-) fetal liver cells. Stat5a/b were also required for optimal induction of Foxp3 in vitro and bound directly to the Foxp3 gene. Reduction of Stat3 in T cells did not reduce the numbers of Treg cells in the thymus or spleen; however, Stat3 was required for IL-6-dependent down-regulation of Foxp3. Therefore, we conclude that Stat5a/b have an essential, nonredundant role in regulating Treg cells, and that Stat3 and Stat5a/b appear to have opposing roles in the regulation of Foxp3.