新功能、新界面、新体验,扫描即可下载生物谷APP!
首页 » 生物研究 » J immunol:STAT2调节树突状细胞交叉呈递

J immunol:STAT2调节树突状细胞交叉呈递

来源:生物谷 2016-05-31 13:46

2016年5月31日 讯 /生物谷BIOON/ --树突状细胞的交叉呈递效应"cross-presentation"能够激活CD8 T细胞抵抗胞内的外源微生物以及并不感染树突状细胞的其它微生物。此外,交叉呈递作用还能够有效激活抗肿瘤T细胞免疫反应。外源微生物特有的分子结构是激活DC的主要元素,激活后的DC能够提高其交叉呈递的效率。

 
此前研究发现,TLR信号引起的DC的交叉呈递效应依赖于MyD88以及I型干扰素。MyD88能够介导NF-KB的激活,进而产生IL-12以及TNF-a等炎性因子;而IFN-I的分泌会激活IFN-R1信号通路,激活胞内的转录因子,包括STAT1,STAT2以及IRF9,从而引发更大量的I型干扰素的分泌,产生正反馈调节。
 
最近,这一假说受到越来越多的证据的挑战,有实验表明TLR-4激活引发的促炎性因子的释放并不依赖于I型干扰素; STAT2参与了TLR-4激活DC引发促炎性因子分泌这一效应,而I型干扰素对此却没有影响;STAT2同时参与了TLR-4引发的巨噬细胞坏死的效应。
 
为了研究STAT-2对DC激活有无影响以及有哪些影响,来自Temple大学的Stefania Gallucci课题组进行了深入研究。相关结果发表在最近一期的《journal of immunology》杂志上。
 
首先,作者比较了野生型小鼠体内的DC与STAT2突变体小鼠体内的DC在受到TLR 配体刺激后的激活情况。结果显示,突变体小鼠DC的MHC-I以及其它共刺激因子的表达量相比野生型有明显的下降。通过RT-PCR实验,作者发现突变体小鼠的DC在刺激之后表达ISG等基因的水平相比野生型也有明显降低。IFNR1缺失突变体小鼠的DC也有相似的表型。
 
进一步,作者发现STAT2或者IFNR1的缺失都会影响DC在受到刺激之后表达CXCL1以及IL-10的能力,然而TNF-a以及IL-6的表达并不受影响。
 
最后,作者通过体外刺激DC并将其与CD8 T细胞共同孵育,通过检测T细胞的激活程度,判断DC交叉呈递的效率。结果显示,STAT缺失突变后的DC在刺激之后交叉呈递的效率缺失有明显降低。体内实验也证明了上述结果。这些试验共同说明STAT2是调控DC激活后提高交叉呈递效率的关键元件。(生物谷Bioon.com)
 
本文系生物谷原创编译整理,欢迎转载!点击 获取授权 。更多资讯请下载生物谷APP.
 
 
PMC:
 
PMID:
 
STAT2 Is Required for TLR-Induced Murine Dendritic Cell Activation and Cross-Presentation
 
Jun Xu, Michael H. Lee, Marita Chakhtoura, Benjamin L. Green, Kevin P. Kotredes, Robert W. Chain, Uma Sriram, Ana M. Gamero and Stefania Gallucci
 
TLR-stimulated cross-presentation by conventional dendritic cells (cDCs) is important in host defense and antitumor immunity. We recently reported that cDCs lacking the type I IFN signaling molecule STAT2 are impaired in cross-presenting tumor Ags to CD8+ T cells. To investigate how STAT2 affects cross-presentation, we determined its requirements for dendritic cell activation. In this study, we report that STAT2 is essential for the activation of murine female cDCs upon TLR3, -4, -7, and -9 stimulation. In response to various TLR ligands, Stat2?/? cDCs displayed reduced expression of costimulatory molecules and type I IFN-stimulated genes. The cDC responses to exogenous IFN-α that we evaluated required STAT2 activation, indicating that the canonical STAT1-STAT2 heterodimers are the primary signaling transducers of type I IFNs in cDCs. Interestingly, LPS-induced production of IL-12 was STAT2 and type I IFN receptor (IFNAR) dependent, whereas LPS-induced production of TNF-α and IL-6 was STAT2 and IFNAR independent, suggesting a specific role of the IFNAR-STAT2 axis in the stimulation of proinflammatory cytokines by LPS in cDCs. In contrast, R848- and CpG-induced cytokine production was less influenced by the IFNAR-STAT2 axis. Short kinetics and IFNAR blockade studies showed that STAT2 main function is to transduce signals triggered by autocrine type I IFNs. Importantly, Stat2?/? cDCs were deficient in cross-presenting to CD8+ T cells in vitro upon IFN-α, CpG, and LPS stimulation, and also in cross-priming and licensing cytotoxic T cell killers in vivo. We conclude that STAT2 plays a critical role in TLR-induced dendritic cell activation and cross-presentation, and thus is vital in host defense.
 
温馨提示:87%用户都在生物谷APP上阅读,扫描立刻下载! 天天精彩!


相关标签

最新会议 培训班 期刊库