Wang Tianhong, Jiang Qiong, Chan Camie, Gorski Kevin S, McCadden Erin, Kardian David, Pardoll Drew, Whartenby Katharine A
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Blood. 2009 Mar 26;113(13):2906-13. doi: 10.1182/blood-2008-08-176354. Epub 2009 Jan 22.
Activation of dendritic cells (DCs) leads to cell maturation, which is accompanied by a regulated pattern of gene expression changes. Two significant and contradictory consequences of DC activation are that, although activation is necessary for maximal T-cell stimulation, it also leads to the initiation of gene expression that results ultimately in cell death. We have identified a gene, MINOR (mitogen-inducible nuclear orphan receptor), that becomes highly up-regulated on activation and whose expression leads to apoptosis in mature DCs. MINOR is a member of the Nur77 family of nuclear orphan receptors, which includes Nur77 and Nurr1. Although Nur77 and Nurr1 are expressed in macrophages and DCs, their expression levels do not change on DC activation. We thus tested the hypothesis that induction of MINOR would lead to an activation-induced cell death in DCs and that its inhibition would increase the lifespan of DCs and improve their vaccine efficacy. To block natural expression of MINOR by DCs, we generated a lentiviral vector that expresses a small interfering RNA. Our results indicate that blockade of MINOR expression dramatically decreases apoptosis in DCs and suggest that this approach may be a novel means to improve the potency of ex vivo-generated DC vaccines.
树突状细胞（DCs）的激活会导致细胞成熟，这伴随着基因表达变化的一种调控模式。DC激活有两个显著且相互矛盾的结果：一方面，激活对于最大程度刺激T细胞是必要的；另一方面，它也会引发基因表达，最终导致细胞死亡。我们鉴定出一个基因，MINOR（丝裂原诱导核孤儿受体），它在激活时高度上调，其表达会导致成熟DCs凋亡。MINOR是核孤儿受体Nur77家族的成员，该家族包括Nur77和Nurr1。尽管Nur77和Nurr1在巨噬细胞和DCs中表达，但它们在DC激活时表达水平不变。因此，我们检验了这样一个假设：MINOR的诱导会导致DCs发生激活诱导的细胞死亡，而对其抑制会延长DCs的寿命并提高其疫苗效力。为了阻断DCs对MINOR的天然表达，我们构建了一个表达小干扰RNA的慢病毒载体。我们的结果表明，阻断MINOR表达可显著减少DCs凋亡，并提示这种方法可能是提高体外产生的DC疫苗效力的一种新手段。
