Schiavoni Giovanna, Mattei Fabrizio, Sestili Paola, Borghi Paola, Venditti Massimo, Morse Herbert C, Belardelli Filippo, Gabriele Lucia
Laboratory of Virology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
J Exp Med. 2002 Dec 2;196(11):1415-25. doi: 10.1084/jem.20021263.
Interferon (IFN) consensus sequence-binding protein (ICSBP) is a transcription factor playing a critical role in the regulation of lineage commitment, especially in myeloid cell differentiation. In this study, we have characterized the phenotype and activation pattern of subsets of dendritic cells (DCs) in ICSBP(-/-) mice. Remarkably, the recently identified mouse IFN-producing cells (mIPCs) were absent in all lymphoid organs from ICSBP(-/-) mice, as revealed by lack of CD11c(low)B220(+)Ly6C(+)CD11b(-) cells. In parallel, CD11c(+) cells isolated from ICSBP(-/-) spleens were unable to produce type I IFNs in response to viral stimulation. ICSBP(-/-) mice also displayed a marked reduction of the DC subset expressing the CD8alpha marker (CD8alpha(+) DCs) in spleen, lymph nodes, and thymus. Moreover, ICSBP(-/-) CD8alpha(+) DCs exhibited a markedly impaired phenotype when compared with WT DCs. They expressed very low levels of costimulatory molecules (intercellular adhesion molecule [ICAM]-1, CD40, CD80, CD86) and of the T cell area-homing chemokine receptor CCR7, whereas they showed higher levels of CCR2 and CCR6, as revealed by reverse transcription PCR. In addition, these cells were unable to undergo full phenotypic activation upon in vitro culture in presence of maturation stimuli such as lipopolysaccharide or poly (I:C), which paralleled with lack of Toll-like receptor (TLR)3 mRNA expression. Finally, cytokine expression pattern was also altered in ICSBP(-/-) DCs, as they did not express interleukin (IL)-12p40 or IL-15, but they displayed detectable IL-4 mRNA levels. On the whole, these results indicate that ICSBP is a crucial factor in the regulation of two possibly linked processes: (a) the development and activity of mIPCs, whose lack in ICSBP(-/-) mice may explain their high susceptibility to virus infections; (b) the generation and activation of CD8alpha(+) DCs, whose impairment in ICSBP(-/-) mice can be responsible for the defective generation of a Th1 type of immune response.
干扰素（IFN）共有序列结合蛋白（ICSBP）是一种转录因子，在谱系定向调控中发挥关键作用，尤其是在髓系细胞分化过程中。在本研究中，我们对ICSBP基因敲除小鼠中树突状细胞（DC）亚群的表型和激活模式进行了表征。值得注意的是，如缺乏CD11c低表达B220阳性Ly6C阳性CD11b阴性细胞所显示的那样，在ICSBP基因敲除小鼠的所有淋巴器官中均不存在最近鉴定出的小鼠干扰素产生细胞（mIPC）。与此同时，从ICSBP基因敲除小鼠脾脏中分离出的CD11c阳性细胞在受到病毒刺激时无法产生I型干扰素。ICSBP基因敲除小鼠脾脏、淋巴结和胸腺中表达CD8α标志物的DC亚群（CD8α阳性DC）也显著减少。此外，与野生型DC相比，ICSBP基因敲除小鼠的CD8α阳性DC表现出明显受损的表型。通过逆转录聚合酶链反应发现，它们共刺激分子（细胞间黏附分子[ICAM]-1、CD40、CD80、CD86）和T细胞区归巢趋化因子受体CCR7的表达水平非常低，而CCR2和CCR6的水平较高。此外，在存在脂多糖或聚肌苷酸:聚胞苷酸等成熟刺激物的体外培养条件下，这些细胞无法进行完全的表型激活，这与缺乏Toll样受体（TLR）3 mRNA表达情况一致。最后，ICSBP基因敲除小鼠的DC中细胞因子表达模式也发生了改变，因为它们不表达白细胞介素（IL）-12p40或IL-15，但可检测到IL-4 mRNA水平。总体而言，这些结果表明ICSBP是调控两个可能相关过程的关键因素：（a）mIPC的发育和活性，ICSBP基因敲除小鼠中缺乏mIPC可能解释了它们对病毒感染的高度易感性；（b）CD8α阳性DC的产生和激活，ICSBP基因敲除小鼠中CD8α阳性DC的损伤可能导致Th1型免疫应答产生缺陷。
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