van Blijswijk Janneke, Schraml Barbara U, Rogers Neil C, Whitney Paul G, Zelenay Santiago, Acton Sophie E, Reis e Sousa Caetano
Immunobiology Laboratory, Cancer Research UK, London Research Institute, London WC2A 3LY, United Kingdom.
Immunobiology Laboratory, Cancer Research UK, London Research Institute, London WC2A 3LY, United Kingdom
J Immunol. 2015 Jan 1;194(1):307-15. doi: 10.4049/jimmunol.1401999. Epub 2014 Nov 19.
Dendritic cells (DCs) are key regulators of innate and adaptive immunity. Our understanding of immune function has benefited greatly from mouse models allowing for selective ablation of DCs. Many such models rely on transgenic diphtheria toxin receptor (DTR) expression driven by DC-restricted promoters. This renders DCs sensitive to DT but is otherwise thought to have no effect on immune physiology. In this study, we report that, unexpectedly, mice in which DTR is expressed on conventional DCs display marked lymph node (LN) hypocellularity and reduced frequency of DCs in the same organs but not in spleen or nonlymphoid tissues. Intriguingly, in mixed bone marrow chimeras the phenotype conferred by DTR-expressing DCs is dominant over control bone marrow-derived cells, leading to small LNs and an overall paucity of DCs independently of the genetic ability to express DTR. The finding of alterations in LN composition and size independently of DT challenge suggests that caution must be exercised when interpreting results of experiments obtained with mouse models to inducibly deplete DCs. It further indicates that DTR, a member of the epidermal growth factor family, is biologically active in mice. Its use in cell ablation experiments needs to be considered in light of this activity.
树突状细胞（DCs）是先天性免疫和适应性免疫的关键调节因子。我们对免疫功能的理解很大程度上受益于能够选择性清除DCs的小鼠模型。许多此类模型依赖于由DC限制性启动子驱动的转基因白喉毒素受体（DTR）表达。这使得DCs对DT敏感，但在其他方面被认为对免疫生理学没有影响。在本研究中，我们意外地发现，在常规DCs上表达DTR的小鼠表现出明显的淋巴结（LN）细胞减少以及同一器官中DCs频率降低，但脾脏或非淋巴组织中未出现这种情况。有趣的是，在混合骨髓嵌合体中，表达DTR的DCs赋予的表型比对照骨髓来源的细胞占优势，导致小的LN以及DCs总体缺乏，这与表达DTR的遗传能力无关。与DT攻击无关的LN组成和大小改变的发现表明，在解释使用小鼠模型诱导清除DCs所获得的实验结果时必须谨慎。这进一步表明，表皮生长因子家族成员DTR在小鼠中具有生物学活性。鉴于这种活性，需要考虑其在细胞消融实验中的应用。
