The Journal of Experimental Medicine
Keystone Symposia
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Published online September 17, 2007
doi:10.1084/jem.20070525
The Journal of Experimental Medicine, Vol. 204, No. 10, 2267-2275
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Iwakoshi et al.
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BRIEF DEFINITIVE REPORT

 The transcription factor XBP-1 is essential for the development and survival of dendritic cells

Neal N. Iwakoshi1,2, Marc Pypaert3, and Laurie H. Glimcher1,4

1 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115
2 Department of Surgery, Emory School of Medicine, Atlanta, GA 30322
3 Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520
4 Department of Medicine, Harvard Medical School, Boston, MA 02115

CORRESPONDENCE Laurie H. Glimcher: lglimche{at}hsph.harvard.edu

Dendritic cells (DCs) play a critical role in the initiation, maintenance, and resolution of an immune response. DC survival is tightly controlled by extracellular stimuli such as cytokines and Toll-like receptor (TLR) signaling, but the intracellular events that translate such extracellular stimuli into life or death for the DC remain poorly understood. The endoplasmic reticulum (ER) stress, or unfolded protein response (UPR), is a signaling pathway that is activated when unfolded proteins accumulate in the ER. The most conserved arm of the UPR involves IRE1{alpha}, an ER transmembrane kinase and endoribonuclease that activates the transcription factor XBP-1 to maintain ER homeostasis and prevent activation of cell death pathways caused by sustained ER stress. We report that XBP-1 is essential for DC development and survival. Lymphoid chimeras lacking XBP-1 possessed decreased numbers of both conventional and plasmacytoid DCs with reduced survival both at baseline and in response to TLR signaling. Overexpression of XBP-1 in hematopoietic progenitors rescued and enhanced DC development. Remarkably, in contrast to other cell types we have examined, the XBP-1 pathway was constitutively activated in immature DCs.


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