Submitted June 26, 2007
Accepted November 2, 2007
In vivo transformation of mouse conventional CD8
+ dendritic cells leads to progressive multisystem histiocytosis
Quynh-Giao Steiner, Luc A Otten*, M John Hicks, Gurkan Kaya, Frederic Grosjean, Estelle Saeuberli, Christine Lavanchy, Friedrich Beermann, Kenneth L McClain, and Hans Acha-Orbea
Depatment of Biochemistry, Faculty of Biology and Medicine, University of Lausanne, Epalinges, Switzerland
Department of Pathology, Baylor College of Medicine, Houston, TX, United States
Department of Dermatology, University of Geneva, Geneva, Switzerland
ISREC, Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Federale de Lausanne, Epalinges, Switzerland
Texas Children's Cancer Center/Hematology Service, Baylor College of Medicine, Houston, TX, United States
* Corresponding author; email: luc.otten{at}hotmail.com.
Division and proliferation of dendritic cells has been proposed to contribute to homeostasis and to prolonged antigen presentation. Whether or not abnormal proliferation of dendritic cells causes Langerhans cell histiocytosis (LCH) is a highly debated topic. Transgenic expression of SV40 T antigens in mature dendritic cells allowed their transformation in vivo while maintaining their phenotype, function and maturation capacity. The transformed cells were differentiated splenic CD8 alpha positive conventional dendritic cells with increased Langerin expression. Their selective transformation was correlated with higher steady state cycling compared to CD8 alpha negative dendritic cells in wild type and transgenic mice. Mice developed a dendritic cell disease involving the spleen, liver, bone marrow, thymus and mesenteric lymph node. Surprisingly, lesions displayed key immunohistological features of Langerhans cell histiocytosis, including expression of Langerin and absence of the abnormal mitoses observed in Langerhans cell sarcomas. Our results demonstrate that a transgenic mouse model with striking similarities to aggressive forms of multisystem histiocytosis like the Letterer-Siwe syndrome can be obtained by transformation of conventional dendritic cells. These findings suggest that conventional dendritic cells may cause some human multisystem LCH. They can reveal shared molecular pathways for human histiocytosis between human and mouse.
