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The transcription factor C/EBPβ orchestrates dendritic cell maturation and functionality under homeostatic and malignant conditions

Item Type:Article
Title:The transcription factor C/EBPβ orchestrates dendritic cell maturation and functionality under homeostatic and malignant conditions
Creators Name:Scholz, F. and Grau, M. and Menzel, L. and Graband, A. and Zapukhlyak, M. and Leutz, A. and Janz, M. and Lenz, G. and Rehm, A. and Höpken, U.E.
Abstract: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.
Keywords:Dendritic Cell Maturation, Transcription Factor C/EBPβ, Lymphoma-Stroma Interaction, Animals, Mice
Source:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
Page Range:26328-26339
Date:20 October 2020
Official Publication:https://doi.org/10.1073/pnas.2008883117
PubMed:View item in PubMed

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