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CCAAT/enhancer-binding protein ? negatively regulates IFN-? expression in T cells.

ABSTRACT: Humoral immunity, including Ab switching and somatic hypermutation, is critically regulated by CD4(+) T cells. T follicular helper (Tfh) cells have been recently shown to be a distinct T cell subset important in germinal center reactions. The transcriptional regulation of Tfh cell development and function has not been well understood. In this study, we report that C/EBP?, a basic region/leucine zipper transcription factor, is highly expressed in Tfh cells. Cebpa-deficient CD4(+) T cells exhibit enhanced IFN-? expression in vitro and in vivo. T cell-specific Cebpa knockout mice, although not defective in Tfh cell generation, produce significantly increased levels of IgG2a/b and IgG3 following immunization with a protein Ag. Moreover, C/EBP? binds to the Ifng gene and inhibits T-bet-driven Ifng transcription in a DNA binding-dependent manner. Our study thus demonstrates that C/EBP? restricts IFN-? expression in T cells to allow proper class switching by B cells.

SUBMITTER: Tanaka S

PROVIDER: S-EPMC4385522 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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CCAAT/enhancer-binding protein α negatively regulates IFN-γ expression in T cells.

Tanaka Shinya S Tanaka Kentaro K Magnusson Fay F Chung Yeonseok Y Martinez Gustavo J GJ Wang Yi-hong YH Nurieva Roza I RI Kurosaki Tomohiro T Dong Chen C

Journal of immunology (Baltimore, Md. : 1950) 20141114 12

Humoral immunity, including Ab switching and somatic hypermutation, is critically regulated by CD4(+) T cells. T follicular helper (Tfh) cells have been recently shown to be a distinct T cell subset important in germinal center reactions. The transcriptional regulation of Tfh cell development and function has not been well understood. In this study, we report that C/EBPα, a basic region/leucine zipper transcription factor, is highly expressed in Tfh cells. Cebpa-deficient CD4(+) T cells exhibit ...[more]

PMID: 25398328

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Project description:α-Synuclein is the main component of Lewy bodies, the intracellular protein aggregates representing the histological hallmark of Parkinson's disease. Elevated α-synuclein levels and mutations in SNCA gene are associated with increased risk for Parkinson's disease. Despite this, little is known about the molecular mechanisms regulating SNCA transcription. CCAAT/enhancer binding protein (C/EBP) β and δ are b-zip transcription factors that play distinct roles in neurons and glial cells. C/EBPβ overexpression increases SNCA expression in neuroblastoma cells and putative C/EBPβ and δ binding sites are present in the SNCA genomic region suggesting that these proteins could regulate SNCA transcription. Based on these premises, the goal of this study was to determine if C/EBPβ and δ regulate the expression of SNCA. We first observed that α-synuclein CNS expression was not affected by C/EBPβ deficiency but it was markedly increased in C/EBPδ-deficient mice. This prompted us to characterize further the role of C/EBPδ in SNCA transcription. C/EBPδ absence led to the in vivo increase of α-synuclein in all brain regions analyzed, both at mRNA and protein level, and in primary neuronal cultures. In agreement with this, CEBPD overexpression in neuroblastoma cells and in primary neuronal cultures markedly reduced SNCA expression. ChIP experiments demonstrated C/EBPδ binding to the SNCA genomic region of mice and humans and luciferase experiments showed decreased expression of a reporter gene attributable to C/EBPδ binding to the SNCA promoter. Finally, decreased CEBPD expression was observed in the substantia nigra and in iPSC-derived dopaminergic neurons from Parkinson patients resulting in a significant negative correlation between SNCA and CEBPD levels. This study points to C/EBPδ as an important repressor of SNCA transcription and suggests that reduced C/EBPδ neuronal levels could be a pathogenic factor in Parkinson's disease and other synucleinopathies and C/EBPδ activity a potential pharmacological target for these neurological disorders.

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CCAAT/enhancer-binding protein ? negatively regulates IFN-? expression in T cells.

Publications

CCAAT/enhancer-binding protein α negatively regulates IFN-γ expression in T cells.

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