Miyagi Takuya, Gil M Pilar, Wang Xin, Louten Jennifer, Chu Wen-Ming, Biron Christine A
Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA.
J Exp Med. 2007 Oct 1;204(10):2383-96. doi: 10.1084/jem.20070401. Epub 2007 Sep 10.
The best-characterized type 1 interferon (IFN) signaling pathway depends on signal transducer and activator of transcription 1 (STAT1) and STAT2. The cytokines can, however, conditionally activate all STATs. Regulation of their access to particular signaling pathways is poorly understood. STAT4 is important for IFN-gamma induction, and NK cells are major producers of this cytokine. We report that NK cells have high basal STAT4 levels and sensitivity to type 1 IFN-mediated STAT4 activation for IFN-gamma production. Increases in STAT1, driven during viral infection by either type 1 IFN or IFN-gamma, are associated with decreased STAT4 access. Both STAT1 and STAT2 are important for antiviral defense, but STAT1 has a unique role in protecting against sustained NK cell IFN-gamma production and resulting disease. The regulation occurs with an NK cell type 1 IFN receptor switch from a STAT4 to a STAT1 association. Thus, a fundamental characteristic of NK cells is high STAT4 bound to the type 1 IFN receptor. The conditions of infection result in STAT1 induction with displacement of STAT4. These studies elucidate the critical role of STAT4 levels in predisposing selection of specific signaling pathways, define the biological importance of regulation within particular cell lineages, and provide mechanistic insights for how this is accomplished in vivo.
特征最明确的1型干扰素（IFN）信号通路依赖于信号转导子和转录激活子1（STAT1）和STAT2。然而，这些细胞因子可以有条件地激活所有的信号转导子和转录激活子（STATs）。目前对它们进入特定信号通路的调控了解甚少。STAT4对IFN-γ的诱导很重要，而自然杀伤细胞（NK细胞）是这种细胞因子的主要产生者。我们报告称，NK细胞具有较高的基础STAT4水平，并且对1型IFN介导的STAT4激活以产生IFN-γ很敏感。在病毒感染期间，由1型IFN或IFN-γ驱动的STAT1增加与STAT4的进入减少有关。STAT1和STAT2对抗病毒防御都很重要，但STAT1在防止NK细胞持续产生IFN-γ及由此导致的疾病方面具有独特作用。这种调控是通过NK细胞1型IFN受体从与STAT4结合转变为与STAT1结合来实现的。因此，NK细胞的一个基本特征是与1型IFN受体结合的STAT4水平较高。感染情况会导致STAT1的诱导以及STAT4的置换。这些研究阐明了STAT4水平在特定信号通路倾向选择中的关键作用，定义了特定细胞谱系内调控的生物学重要性，并为其在体内如何实现提供了机制上的见解。
