Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
J Immunol. 2010 Dec 15;185(12):7252-61. doi: 10.4049/jimmunol.1000672. Epub 2010 Nov 12.
The plastic role of dendritic cells (DCs) in the regulation of immune responses has made them interesting targets for immunotherapy, but also for pathogens or tumors to evade immunity. Functional alterations of DCs are often ascribed to manipulation of canonical NF-κB activity. However, though this pathway has been linked to murine myeloid DC biology, a detailed analysis of its importance in human myeloid DC differentiation, survival, maturation, and function is lacking. The myeloid DC subsets include interstitial DCs and Langerhans cells. In this study, we investigated the role of canonical NF-κB in human myeloid DCs generated from monocytes (monocyte-derived DCs [mo-DCs]) or CD34(+) progenitors (CD34-derived myeloid DCs [CD34-mDCs]). Inhibition of NF-κB activation during and after mo-DC, CD34-interstitial DC, or CD34-Langerhans cell differentiation resulted in apoptosis induction associated with caspase 3 activation and loss of mitochondrial transmembrane potential. Besides regulating survival, canonical NF-κB activity was required for the acquisition of a DC phenotype. Despite phenotypic differences, however, Ag uptake, costimulatory molecule and CCR7 expression, as well as T cell stimulatory capacity of cells generated under NF-κB inhibition were comparable to control DCs, indicating that canonical NF-κB activity during differentiation is redundant for the development of functional APCs. However, both mo-DC and CD34-mDC functionality were reduced by NF-κB inhibition during activation. In conclusion, canonical NF-κB activity is essential for the development and function of mo-DCs as well as CD34-mDCs. Insight into the role of this pathway may help in understanding how pathogens and tumors escape immunity and aid in developing novel treatment strategies aiming to interfere with human immune responses.
树突状细胞 (DCs) 在调节免疫反应中的可塑性使其成为免疫治疗的有趣靶点，但也成为病原体或肿瘤逃避免疫的靶点。DCs 的功能改变通常归因于对经典 NF-κB 活性的操纵。然而，尽管该途径与小鼠髓样 DC 生物学有关，但缺乏对其在人类髓样 DC 分化、存活、成熟和功能中的重要性的详细分析。髓样 DC 亚群包括间质 DC 和朗格汉斯细胞。在这项研究中，我们研究了经典 NF-κB 在单核细胞（单核细胞衍生的 DC [mo-DC]）或 CD34+祖细胞（CD34 衍生的髓样 DC [CD34-mDC]）产生的人类髓样 DC 中的作用。在 mo-DC、CD34 间质 DC 或 CD34 朗格汉斯细胞分化过程中和分化后抑制 NF-κB 激活会导致与 caspase 3 激活和线粒体跨膜电位丧失相关的细胞凋亡诱导。除了调节存活外，经典 NF-κB 活性对于获得 DC 表型也是必需的。然而，尽管表型不同，但在 NF-κB 抑制下生成的细胞的 Ag 摄取、共刺激分子和 CCR7 表达以及 T 细胞刺激能力与对照 DC 相当，表明在分化过程中经典 NF-κB 活性对于功能性 APC 的发展是冗余的。然而，在激活过程中抑制 NF-κB 会降低 mo-DC 和 CD34-mDC 的功能。总之，经典 NF-κB 活性对于 mo-DC 和 CD34-mDC 的发育和功能都是必需的。深入了解该途径的作用可能有助于了解病原体和肿瘤如何逃避免疫，并有助于开发旨在干扰人类免疫反应的新型治疗策略。
