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

Nature Immunology volume 16, pages 708717 (2015) | Download Citation

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.

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Acknowledgements

We thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine for use of the Center for Biomedical Informatics and Multiplex Gene Analysis Genechip Core Facility. Supported by the Howard Hughes Medical Institute, the US National Institutes of Health (1F31CA189491-01 to G.E.G.-R. and K08AI106953 to M.H.), the American Heart Association (12PRE12050419 to W.K.), and the National Cancer Institute (P30 CA91842; for support of the Alvin J. Siteman Cancer Center).

Author information

Affiliations

  1. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Gary E Grajales-Reyes
    • , Arifumi Iwata
    • , Xiaodi Wu
    • , Roxane Tussiwand
    • , Wumesh KC
    • , Nicole M Kretzer
    • , Carlos G Briseño
    • , Vivek Durai
    • , Prachi Bagadia
    • , Malay Haldar
    • , Theresa L Murphy
    •  & Kenneth M Murphy
  2. Department of Medicine A, Hematology and Oncology, University of Muenster, Muenster, Germany.

    • Jörn Albring
  3. Department of Biomedicine, University of Basel, Basel, Switzerland.

    • Roxane Tussiwand
  4. Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.

    • Jörg Schönheit
  5. Institute of Molecular Tumor Biology, University of Münster, Münster, Germany.

    • Frank Rosenbauer
  6. Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Kenneth M Murphy

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Contributions

G.E.G.-R., T.L.M. and K.M.M. designed the study; G.E.G.-R., A.I., J.A., R.T. and T.L.M. performed experiments related to cell sorting, retroviral infection, culture and flow cytometry, with advice from N.M.K., C.G.B., V.D., P.B. and M.H.; W.K. performed experiments related to antibody generation and Irf8 ChIP-Seq; A.I. performed and analyzed ChIP-Seq experiments; G.E.G.-R. performed microarray experiments with advice from and analysis by X.W. and C.G.B.; J.S. and F.R. provided Irf8VENUS mice and advice; and G.E.G.-R., X.W., T.L.M. and K.M.M. wrote the manuscript with contributions from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Kenneth M Murphy.

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https://doi.org/10.1038/ni.3197

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