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Compensatory dendritic cell development mediated by BATF–IRF interactions

Nature volume 490, pages 502–507 (2012)Cite this article

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Abstract

The AP1 transcription factor Batf3 is required for homeostatic development of CD8α+ classical dendritic cells that prime CD8 T-cell responses against intracellular pathogens. Here we identify an alternative, Batf3-independent pathway in mice for CD8α+ dendritic cell development operating during infection with intracellular pathogens and mediated by the cytokines interleukin (IL)-12 and interferon-γ. This alternative pathway results from molecular compensation for Batf3 provided by the related AP1 factors Batf, which also functions in T and B cells, and Batf2 induced by cytokines in response to infection. Reciprocally, physiological compensation between Batf and Batf3 also occurs in T cells for expression of IL-10 and CTLA4. Compensation among BATF factors is based on the shared capacity of their leucine zipper domains to interact with non-AP1 factors such as IRF4 and IRF8 to mediate cooperative gene activation. Conceivably, manipulating this alternative pathway of dendritic cell development could be of value in augmenting immune responses to vaccines.

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Figure 1: Intracellular pathogens or IL-12 restore lymphoid CD8α + cDCs and tissue-resident CD103 + cDCs in Batf3 −/− mice.
Figure 2: IL-12-induced CD8α + cDCs in Batf3 −/− mice can cross-present and mediate tumour rejection.
Figure 3: Batf compensates for CD8α + cDC development in Batf3 −/− mice.
Figure 4: Batf2 compensates for Batf3 in CD8α + and CD103 + cDC development during T. gondii infection.
Figure 5: BATF leucine zipper interactions with non-AP1 factors mediate lineage-specific actions.

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Gene Expression Omnibus

Data deposits

All original microarray data have been deposited in NCBI’s Gene Expression Omnibus under accession number GSE40647.

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Acknowledgements

This work was supported by the Howard Hughes Medical Institute, National Institutes of Health (AI076427-02) and Department of Defense (W81XWH-09-1-0185) (K.M.M.), the American Heart Association (12PRE8610005) (A.T.S.), German Research Foundation (AL 1038/1-1) (J.C.A), American Society of Hematology Scholar Award and Burroughs Welcome Fund Career Award for Medical Scientists (B.T.E.), and Cancer Research Institute predoctoral fellowship (W.-L.L.). We thank the ImmGen consortium34, M. White for blastocyst injections and generation of mouse chimaeras, 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. The Siteman Cancer Center is supported in part by the NCI Cancer Center Support Grant P30 CA91842. IL-12 was a gift from Pfizer.

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  1. Roxane Tussiwand, Wan-Ling Lee and Theresa L. Murphy: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA,

    Roxane Tussiwand, Wan-Ling Lee, Theresa L. Murphy, Mona Mashayekhi, Wumesh KC, Jörn C. Albring, Ansuman T. Satpathy, Jeffrey A. Rotondo, Brian T. Edelson, Nicole M. Kretzer, Xiaodi Wu, Samuel S. K. Lam, Cora T. Aurthur, Robert D. Schreiber & Kenneth M. Murphy

  2. Department of Molecular Microbiology, Washington University School of Medicine, St Louis, 63110, Missouri, USA

    Leslie A. Weiss, Michael Behnke, Christina L. Stallings & L. David Sibley

  3. Department of Discovery Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA,

    Elke Glasmacher & Harinder Singh

  4. Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, 20892-1674, Maryland, USA

    Peng Li, Wei Liao & Warren J. Leonard

  5. Howard Hughes Medical Institute, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA,

    Kenneth M. Murphy

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Contributions

R.T., W.-L.L., T.L.M. and M.M. performed experiments with Batf−/−, Batf2−/−, Batf3−/− and double-knockout mice; T.L.M. made and analysed all BATF mutants; J.A.R. aided with EMSAs; W.KC, J.C.A. and A.T.S. were involved with microarray analysis and generation of mutant mice. J.C.A. was involved in generating of Batf2−/− mice. B.T.E. was involved with L. monocytogenes analysis; N.M.K was involved with cross-presentation analysis. X.W. was involved with bioinformatic analysis; L.A.W. and C.L.S. were involved with M. tuberculosis infection; E.G. and H.S. helped to identify EMSA probes; P.L., W.L. and W.J.L. performed ChIP-seq and helped to identify EMSA probes; M.B. and L.D.S. aided with T. gondii infections; S.S.K.L., C.T.A. and R.D.S. aided with tumour models. H.S. and W.J.L. provided helpful discussions. K.M.M. directed the work and wrote the manuscript. All authors discussed the results and contributed to the manuscript.

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Correspondence to Kenneth M. Murphy.

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Tussiwand, R., Lee, WL., Murphy, T. et al. Compensatory dendritic cell development mediated by BATF–IRF interactions. Nature 490, 502–507 (2012). https://doi.org/10.1038/nature11531

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