The transcription factor C/EBPβ orchestrates dendritic cell maturation and functionality under homeostatic and malignant conditions
| Autor: | Uta E. Höpken, Annika Graband, Lutz Menzel, Myroslav Zapukhlyak, Georg Lenz, Michael Grau, Achim Leutz, Armin Rehm, Martin Janz, Florian Scholz |
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| Rok vydání: | 2020 |
| Předmět: |
Male
T-Lymphocytes chemical and pharmacologic phenomena Mice Transgenic Cell fate determination Monocytes Cell Line Mice Tumor Microenvironment Animals Humans Protein Isoforms E2F1 E2F Transcription factor Cyclin-dependent kinase 1 Multidisciplinary Chemistry CCAAT-Enhancer-Binding Protein-beta TOR Serine-Threonine Kinases Cell Differentiation Dendritic Cells Dendritic cell Biological Sciences Cell cycle Cell biology Mice Inbred C57BL Gene Expression Regulation Female Signal transduction Signal Transduction Transcription Factors |
| Zdroj: | Proc Natl Acad Sci U S A |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.2008883117 |
| Popis: | Dendritic cell (DC) maturation is a prerequisite for the induction of adaptive immune responses against pathogens and cancer. Transcription factor (TF) networks control differential aspects of early DC progenitor versus late-stage DC cell fate decisions. Here, we identified the TF C/EBPβ as a key regulator for DC maturation and immunogenic functionality under homeostatic and lymphoma-transformed conditions. Upon cell-specific deletion of C/EBPβ in CD11c(+)MHCII(hi) DCs, gene expression profiles of splenic C/EBPβ(−/−) DCs showed a down-regulation of E2F cell cycle target genes and associated proliferation signaling pathways, whereas maturation signatures were enriched. Total splenic DC cell numbers were modestly increased but differentiation into cDC1 and cDC2 subsets were unaltered. The splenic CD11c(+)MHCII(hi)CD64(+) DC compartment was also increased, suggesting that C/EBPβ deficiency favors the expansion of monocytic-derived DCs. Expression of C/EBPβ could be mimicked in LAP/LAP* isoform knockin DCs, whereas the short isoform LIP supported a differentiation program similar to deletion of the full-length TF. In accordance with E2F1 being a negative regulator of DC maturation, C/EBPβ(−/−) bone marrow-derived DCs matured much faster enabling them to activate and polarize T cells stronger. In contrast to a homeostatic condition, lymphoma-exposed DCs exhibited an up-regulation of the E2F transcriptional pathways and an impaired maturation. Pharmacological blockade of C/EBPβ/mTOR signaling in human DCs abrogated their protumorigenic function in primary B cell lymphoma cocultures. Thus, C/EBPβ plays a unique role in DC maturation and immunostimulatory functionality and emerges as a key factor of the tumor microenvironment that promotes lymphomagenesis. |
| Databáze: | OpenAIRE |
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