Notch2 integrates signaling by the transcription factors RBP-J and CREB1 to promote T cell cytotoxicity

Yoichi Maekawa; Yoshiaki Minato; Chieko Ishifune; Takeshi Kurihara; Akiko Kitamura; Hidefumi Kojima; Hideo Yagita; Mamiko Sakata-Yanagimoto; Toshiki Saito; Ichiro Taniuchi; Shigeru Chiba; Saburo Sone; Koji Yasutomo

doi:10.1038/ni.1649

Notch2 integrates signaling by the transcription factors RBP-J and CREB1 to promote T cell cytotoxicity

Nat Immunol. 2008 Oct;9(10):1140-7. doi: 10.1038/ni.1649. Epub 2008 Aug 24.

Authors

Yoichi Maekawa¹, Yoshiaki Minato, Chieko Ishifune, Takeshi Kurihara, Akiko Kitamura, Hidefumi Kojima, Hideo Yagita, Mamiko Sakata-Yanagimoto, Toshiki Saito, Ichiro Taniuchi, Shigeru Chiba, Saburo Sone, Koji Yasutomo

Affiliation

¹ Department of Immunology & Parasitology, Tokushima, Japan.

PMID: 18724371
DOI: 10.1038/ni.1649

Abstract

The acquisition of cytotoxic effector function by CD8(+) T cells is crucial for the control of intracellular infection and tumor invasion. However, it remains unclear which signaling pathways are required for the differentiation of CD8(+) cytotoxic T lymphocytes. We show here that Notch2-deficient T cells had impaired differentiation into cytotoxic T lymphocytes. In addition, dendritic cells with lower expression of the Notch ligand Delta-like 1 induced the differentiation of cytotoxic T lymphocytes less efficiently. We found that the intracellular domain of Notch2 interacted with a phosphorylated form of the transcription factor CREB1, and together these proteins bound the transcriptional coactivator p300 to form a complex on the promoter of the gene encoding granzyme B. Our results suggest that the highly regulated, dynamic control of T cell cytotoxicity depends on the integration of Notch2 and CREB1 signals.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / immunology
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
Cell Differentiation / immunology*
Cyclic AMP Response Element-Binding Protein / immunology
Cyclic AMP Response Element-Binding Protein / metabolism*
Dendritic Cells / immunology
Female
Gene Expression Regulation / immunology
Granzymes / genetics
Immunoglobulin J Recombination Signal Sequence-Binding Protein
Lymphocyte Activation / immunology
Mice
Mice, Inbred C57BL
Polymerase Chain Reaction
Promoter Regions, Genetic
Receptor, Notch2 / immunology
Receptor, Notch2 / metabolism*
Signal Transduction / immunology*
T-Lymphocytes, Cytotoxic / cytology*
T-Lymphocytes, Cytotoxic / immunology
Transcription, Genetic / immunology
p300-CBP Transcription Factors / immunology
p300-CBP Transcription Factors / metabolism

Substances

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Creb1 protein, mouse
Cyclic AMP Response Element-Binding Protein
Immunoglobulin J Recombination Signal Sequence-Binding Protein
Notch2 protein, mouse
Rbpj protein, mouse
Receptor, Notch2
p300-CBP Transcription Factors
Granzymes