Batf3 maintains autoactivation of Irf8 for commitment of a CD8α + conventional DC clonogenic progenitor

Gary E. Grajales-Reyes, Arifumi Iwata, Jörn Albring, Xiaodi Wu, Roxane Tussiwand, Wumesh Kc, Nicole M. Kretzer, Carlos G. Briseño, Vivek Durai, Prachi Bagadia, Malay Haldar, Jörg Schönheit, Frank Rosenbauer, Theresa L. Murphy, Kenneth M. Murphy

Research output: Contribution to journalArticle

153 Scopus citations

Abstract

The transcription factors Batf3 and IRF8 are required for the development of CD8α + conventional dendritic cells (cDCs), but the basis for their actions has remained unclear. Here we identified two progenitor cells positive for the transcription factor Zbtb46 that separately generated CD8α + cDCs and CD4 + cDCs and arose directly from the common DC progenitor (CDP). Irf8 expression in CDPs required prior autoactivation of Irf8 that was dependent on the transcription factor PU.1. Specification of the clonogenic progenitor of CD8α + cDCs (the pre-CD8 DC) required IRF8 but not Batf3. However, after specification of pre-CD8 DCs, autoactivation of Irf8 became Batf3 dependent at a CD8α + cDC-specific enhancer with multiple transcription factor AP1-IRF composite elements (AICEs) within the Irf8 superenhancer. CDPs from Batf3 mice that were specified toward development into pre-CD8 DCs failed to complete their development into CD8α + cDCs due to decay of Irf8 autoactivation and diverted to the CD4 + cDC lineage.

Original languageEnglish
Pages (from-to)708-717
Number of pages10
JournalNature immunology
Volume16
Issue number7
DOIs
StatePublished - Jul 20 2015

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    Grajales-Reyes, G. E., Iwata, A., Albring, J., Wu, X., Tussiwand, R., Kc, W., Kretzer, N. M., Briseño, C. G., Durai, V., Bagadia, P., Haldar, M., Schönheit, J., Rosenbauer, F., Murphy, T. L., & Murphy, K. M. (2015). Batf3 maintains autoactivation of Irf8 for commitment of a CD8α + conventional DC clonogenic progenitor. Nature immunology, 16(7), 708-717. https://doi.org/10.1038/ni.3197