Characterization of BATF functions in plasmacytoid dendritic cell development and type I interferon production in antiviral immune responses
Final Report Abstract
Plasmacytoid dendritic cells (pDCs) can produce large amounts of type I interferons (IFN). Thus, pDCs play an important and complex role in infections, mediating protective immune responses or causing immunopathology. The cellular and molecular mechanisms underlying pDC-mediated immune regulation remain poorly understood. Searching for novel regulators of pDC effector functions, we found that the basic leucine zipper transcription factor ATF-like (BATF) is highly expressed in IFNβ-producing pDCs, although it has not previously been implicated in pDC differentiation or function. To assess the impact of BATF on the expression of type I IFN, we utilised Batf-deficient mice. In comparison to wild-type (WT) littermates, BM-derived pDCs from BATF-/- mice exhibited increased production of type I IFN at both the mRNA and protein levels following CpG stimulation in vitro. In vivo, Batf-/- mice exhibit elevated serum levels of type I IFN at an early stage following CpG injection and LCMV infection, in comparison to WT animals. A multi-omics approach was employed to elucidate the transcriptional and epigenetic differences between Batf+/+ and Batf-/- pDCs, in conjunction with genome-wide BATF-ChIP-Seq. This revealed an indirect mode of action of BATF-mediated IFN I regulation and identified the zinc-finger transcription factor DC-SCRIPT as a novel BATF target gene with the capacity to directly repress IFN I expression in pDCs. Our findings indicate that BATF plays a previously unidentified role in regulating pDC-dependent type I IFN responses by controlling the expression of the transcriptional regulator DC-SCRIPT, which interacts with the transcription factor IRF7, thereby suppressing its transcriptional activities. Furthermore, the bone marrow (BM) and secondary lymphoid organs of Batf-/- mice exhibited augmented frequencies of mature pDCs and multiple pDC-precursor populations in comparison to Batf+/+ mice. Conversely, the over-expression of Batf in the Hoxb8-Fl progenitor cell line reciprocated the results of the ex vivo and in vitro findings in BATF-deficiency. Our data indicate that BATF plays a pivotal role in regulating the developmental potential of DC progenitors and maintaining the homeostasis of DC subsets by modulating the expression levels of downstream transcription factors that determine the fate of DCs. These findings significantly contribute to our understanding of the molecular mechanisms underlying pDC development and the regulation of type I IFN expression in pDCs in anti-infectious immune responses, as well as having relevance for type I IFN-mediated autoimmunity.
Publications
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Dendritic Cells: Neglected Modulators of Peripheral Immune Responses and Neuroinflammation in Mood Disorders?. Cells, 10(4), 941.
Leite, Dantas Rafael; Freff, Jana; Ambrée, Oliver; Beins, Eva C.; Forstner, Andreas J.; Dannlowski, Udo; Baune, Bernhard T.; Scheu, Stefanie & Alferink, Judith
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The transcription factor reservoir and chromatin landscape in activated plasmacytoid dendritic cells. BMC Genomic Data, 22(1).
Mann-Nüttel, Ritu; Ali, Shafaqat; Petzsch, Patrick; Köhrer, Karl; Alferink, Judith & Scheu, Stefanie
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Dendritic cell functions in vivo: A user's guide to current and next‐ generation mutant mouse models. European Journal of Immunology, 52(11), 1712-1749.
Dalod, Marc & Scheu, Stefanie
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Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML. Cancer Discovery, 12(6), 1560-1579.
Salmon, Jessica M.; Todorovski, Izabela; Stanley, Kym L.; Bruedigam, Claudia; Kearney, Conor J.; Martelotto, Luciano G.; Rossello, Fernando; Semple, Timothy; Arnau, Gisela Mir; Zethoven, Magnus; Bots, Michael; Bjelosevic, Stefan; Cluse, Leonie A.; Fraser, Peter J.; Litalien, Veronique; Vidacs, Eva; McArthur, Kate; Matthews, Antony Y.; Gressier, Elise ... & Johnstone, Ricky W.
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Guidelines for mouse and human DC generation. European Journal of Immunology, 53(11).
Lutz, Manfred B.; Ali, Shafaqat; Audiger, Cindy; Autenrieth, Stella E.; Berod, Luciana; Bigley, Venetia; Cyran, Laura; Dalod, Marc; Dörrie, Jan; Dudziak, Diana; Flórez‐Grau, Georgina; Giusiano, Lucila; Godoy, Gloria J.; Heuer, Marion; Krug, Anne B.; Lehmann, Christian H. K.; Mayer, Christian T.; Naik, Shalin H.; Scheu, Stefanie ... & Zenke, Martin
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BATF controls IFN I production via DC-SCRIPT in plasmacytoid dendritic cells.
Ali, Shafaqat; Mann-Nüttel, Ritu; Marson, Marcel; Leiser, Ben; Hoffe, Jasmina; Dress, Regine J.; Bhuyan, Mahamudul Hasan; Petzsch, Patrick; Köhrer, Karl; Xu, Haifeng C.; Lang, Philipp A.; Zhang, Shengbo; Chopin, Michaël; Nutt, Stephen L.; Alferink, Judith & Scheu, Stefanie
