CISH is induced during DC development and regulates DC-mediated CTL activation
CISH is induced during DC development and regulates DC-mediated CTL activation
复制标题
DOI：
10.1002/eji.201141846
复制
发表时间：
2012-01-01
影响因子：
5.4
通讯作者：
Bae, Yong-Soo
中科院分区：
文献类型：
--
作者：
Miah, Mohammad Alam;Yoon, Cheol-Hee;Bae, Yong-Soo
细胞因子诱导型SH 2结构域蛋白（CISH）是一个众所周知的STAT 5靶基因，但其在免疫系统中的作用仍不确定。在这项研究中，我们发现CISH主要是诱导树突状细胞（DC）从小鼠骨髓（BM）细胞的发展，并在1型DC的发展和DC介导的CTL激活中起着至关重要的作用。CISH基因敲低可降低BMDCs中MHC I类分子、共刺激分子和促炎细胞因子的表达。同时，CISH基因敲低通过激活细胞周期和减少细胞凋亡而显著提高DC产量。发现DC发育后期细胞增殖的下调与CISH介导的STAT 5激活的负反馈调节有关。在T细胞免疫中，OT-1 T细胞增殖显著降低CISH敲低在DC中，而OT-2 T细胞增殖不受CISH敲低的影响。DC疫苗接种产生的CTL也因CISH敲低而显著减少，随后基于DC的肿瘤免疫治疗显著受损。综上所述，我们的数据表明，CISH表达在DC发育的后期触发DC祖细胞增殖的关闭，并促进DC分化为CTL的有效刺激物。
The cytokine inducible SH2-domain protein (CISH) is a well-known STAT5 target gene, but its role in the immune system remains uncertain. In this study, we found that CISH is predominantly induced during dendritic cell (DC) development from mouse bone marrow (BM) cells and plays a crucial role in type 1 DC development and DC-mediated CTL activation. CISH knockdown reduced the expression of MHC class I, co-stimulatory molecules and pro-inflammatory cytokines in BMDCs. Meanwhile, the DC yield was markedly enhanced by CISH knockdown via cell-cycle activation and reduction of cell apoptosis. Down-regulation of cell proliferation at the later stage of DC development was found to be associated with CISH-mediated negative feedback regulation of STAT5 activation. In T-cell immunity, OT-1 T-cell proliferation was significantly reduced by CISH knockdown in DCs, whereas OT-2 T-cell proliferation was not affected by CISH knockdown. CTLs generated by DC vaccination were also markedly reduced by CISH knockdown, followed by significant impairment of DC-based tumor immunotherapy. Taken together, our data suggest that CISH expression at the later stage of DC development triggers the shutdown of DC progenitor cell proliferation and facilitates DC differentiation into a potent stimulator of CTLs.