Universität zu Köln

Scholz, Florian, Grau, Michael ORCID: 0000-0003-1909-0133, Menzel, Lutz, Graband, Annika, Zapukhlyak, Myroslav, Leutz, Achim ORCID: 0000-0001-8259-927X, Janz, Martin, Lenz, Georg, Rehm, Armin and Hoepken, Uta E. (2020). The transcription factor C/EBP beta orchestrates dendritic cell maturation and functionality under homeostatic and malignant conditions. Proc. Natl. Acad. Sci. U. S. A., 117 (42). S. 26328 - 26340. WASHINGTON: NATL ACAD SCIENCES. ISSN 0027-8424

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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/EBP beta as a key regulator for DC maturation and immunogenic functionality under homeostatic and lymphoma-transformed conditions. Upon cell-specific deletion of C/EBP beta in CD11c(+)MHCII(hi) DCs, gene expression profiles of splenic C/EBP beta(-/-) 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/EBP beta deficiency favors the expansion of monocytic-derived DCs. Expression of C/EBP beta 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/EBP beta(-/-) 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/EBP beta/mTOR signaling in human DCs abrogated their protumorigenic function in primary B cell lymphoma cocultures. Thus, C/EBP beta plays a unique role in DC maturation and immunostimulatory functionality and emerges as a key factor of the tumor microenvironment that promotes lymphomagenesis.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Scholz, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Grau, Michael UNSPECIFIED orcid.org/0000-0003-1909-0133 UNSPECIFIED Menzel, Lutz UNSPECIFIED UNSPECIFIED UNSPECIFIED Graband, Annika UNSPECIFIED UNSPECIFIED UNSPECIFIED Zapukhlyak, Myroslav UNSPECIFIED UNSPECIFIED UNSPECIFIED Leutz, Achim UNSPECIFIED orcid.org/0000-0001-8259-927X UNSPECIFIED Janz, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Lenz, Georg UNSPECIFIED UNSPECIFIED UNSPECIFIED Rehm, Armin UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoepken, Uta E. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-314578
DOI:	10.1073/pnas.2008883117
Journal or Publication Title:	Proc. Natl. Acad. Sci. U. S. A.
Volume:	117
Number:	42
Page Range:	S. 26328 - 26340
Date:	2020
Publisher:	NATL ACAD SCIENCES
Place of Publication:	WASHINGTON
ISSN:	0027-8424
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MHC CLASS-II; GENE-EXPRESSION; ANTIGEN PRESENTATION; DIFFERENTIATION; IDENTIFICATION; MACROPHAGES; CYCLE; RISE; PROLIFERATION; SIGNATURES Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/31457