Transcription factor C/EBPβ orchestrates DC maturation and functionality under homeostatic and malignant conditions [CEBPbetaKO]

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. Gene expression profiles of splenic C/EBPβ-/- DCs showed a strong downregulation of E2F cell cycle target genes, whereas signatures of maturation were enriched. In accordance with E2F1 being a negative regulator of DC maturation, C/EBPβ-/- bone marrow-derived DCs matured much faster enabling them to strongly activate T cells. Conversely, the E2F transcriptional pathways were upregulated in lymphoma-exposed DCs and DC maturation was impaired. Pharmacological blockade of C/EBPβ/mTOR signaling in human DCs abrogated their pro-tumorigenic function in B-cell lymphoma co-cultures. Thus, C/EBPβ plays a unique role in DC maturation and functionality and emerges as a key factor of the microenvironment promoting lymphomagenesis. To test the role of C/EBPβ in the regulation of DC maturation and cell fate decision under homeostatic conditions, we employed genome-wide expression profiling of C/EBPβ-proficient and C/EBPβ-deficient murine DC cells. Splenic CD11c+MHCII+ DCs were sorted from CD11c-Cre-eGFP (C/EBPβ+/+) and from CD11c-Cre-eGFPxC/EBPβflox/flox (C/EBPβ-/-) mice. Furthermore, a downregulation of C/EBPβ was recently observed, when we exposed DCs to lymphoma cells in the murine aggressive Myc-driven B cell lymphoma model. Based on these data, we analyzed whole genome transcriptional changes in DCs upon exposure to Eµ-Myc lymphoma cells.